{"gene":"MLLT10","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1995,"finding":"AF10 (MLLT10) contains a novel cysteine-rich motif termed the LAP/PHD finger (Leukemia-Associated Protein finger), which is proposed to bind zinc and function as a DNA-binding domain; this domain is disrupted in leukemia-associated chromosomal translocations.","method":"Sequence homology analysis and structural characterization of zinc finger motifs across multiple proteins","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 4 — computational/sequence-based prediction without direct biochemical validation of zinc binding or DNA binding in this paper","pmids":["7568208"],"is_preprint":false},{"year":1995,"finding":"AF10 contains conserved zinc finger and leucine zipper domains; in MLL-AF10 fusions resulting from t(10;11), the leucine zipper motif of AF10 is consistently juxtaposed onto the N-terminal region of MLL (HRX), suggesting a critical role for this leucine zipper dimerization motif in the chimeric oncoproteins.","method":"Reverse transcriptase-PCR and sequence analysis of leukemia patient samples","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 3 — molecular characterization across 8 cases consistently showing leucine zipper retention, but no direct functional assay of the motif in this paper","pmids":["7662954"],"is_preprint":false},{"year":1996,"finding":"AF10 is fused to CALM (PICALM) in the t(10;11)(p13;q14) translocation in U937 cells, generating the CALM-AF10 fusion oncoprotein; CALM shares high homology with the murine ap-3 clathrin assembly protein and has a high-affinity binding site for phosphoinositols.","method":"Positional cloning and candidate gene approach; sequence analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — foundational cloning study, highly cited, identified the fusion gene and characterized CALM's clathrin-assembly domain","pmids":["8643484"],"is_preprint":false},{"year":2000,"finding":"The extended LAP/PHD-finger domain of AF10 mediates homo-oligomerization of the protein (demonstrated with recombinant AF10); AF10 also binds cruciform DNA via an AT-hook motif and localizes to the nucleus via a defined bipartite nuclear localization signal in its N-terminal region.","method":"Biochemical analysis with recombinant protein; DNA binding assays; subcellular fractionation","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro biochemical reconstitution with recombinant protein demonstrating oligomerization and DNA binding; multiple orthogonal methods","pmids":["10860745"],"is_preprint":false},{"year":2001,"finding":"The leucine zipper domain of AF10 interacts with GAS41 (a glioblastoma amplified gene product homologous to yeast ANC1 and MLL fusion partners AF9/ENL); this interaction was confirmed by co-immunoprecipitation. Furthermore, GAS41 interacts with INI1 (SNF5 homolog, a SWI/SNF chromatin remodeling complex component), and INI1 was detected in AF10 immunoprecipitates, linking AF10 to SWI/SNF-mediated chromatin remodeling.","method":"Yeast two-hybrid screen followed by co-immunoprecipitation from cell line extracts","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid confirmed by reciprocal co-IP; multiple interaction partners identified","pmids":["11756182"],"is_preprint":false},{"year":2001,"finding":"The synovial sarcoma-associated protein SYT physically interacts with AF10; the N-terminal region of SYT interacts with the C-terminal region of AF10 (outside known functional domains), confirmed by yeast two-hybrid, co-immunoprecipitation of endogenous and epitope-tagged proteins, and colocalization in transfected cells.","method":"Yeast two-hybrid screen; co-immunoprecipitation; colocalization by fluorescence microscopy","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple orthogonal confirmation methods (Y2H + co-IP + colocalization), single lab","pmids":["11423977"],"is_preprint":false},{"year":2001,"finding":"The Drosophila AF10 homolog (dAF10/Alhambra) functions in heterochromatin-dependent gene silencing and interacts physically with Heterochromatin Protein 1 (HP1) both in vitro and in vivo, placing dAF10 in the heterochromatin-dependent silencing pathway.","method":"Genetic suppressor/enhancer analysis of position effect variegation; in vitro pull-down and in vivo co-immunoprecipitation with HP1","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic functional assay plus biochemical interaction confirmation, ortholog in Drosophila","pmids":["11266362"],"is_preprint":false},{"year":2002,"finding":"The AF10 leucine zipper (a conserved 82-amino acid region comprising two adjacent alpha-helical domains) is necessary and sufficient for leukemic transformation by MLL-AF10; deletion of the 29-amino acid leucine zipper completely abrogated immortalizing and transforming activity. The same domain confers transcriptional activation properties on MLL-AF10.","method":"Retroviral transduction of primary murine myeloid progenitors; serial replating assays; in vivo leukemia induction; structure-function mutagenesis; transcriptional activation assays with GAL4 fusions","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — rigorous structure-function analysis with multiple deletion mutants, in vitro and in vivo assays, replicated across constructs","pmids":["11986236"],"is_preprint":false},{"year":2003,"finding":"The leucine zipper domain of Drosophila AF10 (ALH) activates Polycomb group-responsive elements (PREs) when overexpressed in isolation, while the full-length protein does not (the PHD domain inhibits this activity); this derepression activity is conserved in the human AF10 leucine zipper expressed in Drosophila, and the MLL-AF10 fusion (which lacks the PHD domain) similarly activates PREs.","method":"Drosophila genetics; overexpression of isolated domains vs. full-length protein; PRE reporter assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — functional domain dissection in Drosophila model with clear epistatic relationship between PHD and LZ domains","pmids":["12482966"],"is_preprint":false},{"year":2006,"finding":"CALM-AF10 fusion causes leukemic transformation by upregulating Hoxa5 through recruitment of hDOT1L (H3K79 methyltransferase); hDOT1L interacts with AF10 and contributes to CALM-AF10-mediated leukemogenesis by (1) preventing nuclear export of CALM-AF10 and (2) upregulating Hoxa5 via H3K79 methylation.","method":"Retroviral transduction/bone marrow transformation assays; co-immunoprecipitation; ChIP; shRNA knockdown of hDOT1L; gene expression analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (co-IP, ChIP, functional transformation assay, knockdown rescue), highly cited foundational study","pmids":["16921363"],"is_preprint":false},{"year":2006,"finding":"CATS (CALM interacting protein expressed in thymus and spleen), identified via yeast two-hybrid using the N-terminal half of CALM as bait, interacts with CALM at amino acids 221-335. CATS localizes to the nucleus/nucleolus and its expression markedly increases nuclear localization of both CALM and the leukemogenic CALM/AF10 fusion protein.","method":"Yeast two-hybrid screen; pull-down assays; co-immunoprecipitation; colocalization by fluorescence microscopy; subcellular localization analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple confirmation methods for interaction and localization effect, single lab","pmids":["16491119"],"is_preprint":false},{"year":2007,"finding":"AF10 interacts with the lymphoid transcription factor Ikaros via AF10's leucine zipper domain (confirmed by GST pull-down and co-immunoprecipitation); coexpression of CALM/AF10 (but not AF10 alone) alters the subcellular localization of Ikaros in murine fibroblasts, and AF10 reduces the transcriptional repressor activity of Ikaros.","method":"Yeast two-hybrid screen; GST pull-down; co-immunoprecipitation; subcellular localization by fluorescence microscopy; transcriptional repressor activity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple methods confirming interaction and functional consequence on Ikaros activity","pmids":["18037964"],"is_preprint":false},{"year":2007,"finding":"AF10-mediated transcription is enhanced by its interaction with FLRG (follistatin-related gene); the N-terminal PHD domain of AF10 mediates this interaction; FLRG promotes homo-oligomerization of AF10 and enhances AF10-mediated transactivation in reporter assays.","method":"Yeast two-hybrid screen; far-Western blot; co-immunoprecipitation; transactivation assays (Gal4-AF10 fusion in transfection)","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2-3 — interaction confirmed by multiple methods; functional consequence on transcription shown by reporter assay","pmids":["17868029"],"is_preprint":false},{"year":2009,"finding":"The CALM-AF10 fusion protein globally reduces H3K79 methylation in leukemic cells by disrupting the normal AF10-mediated association of hDOT1L with chromatin, while simultaneously causing local H3K79 hypermethylation at Hoxa5 loci; cells with reduced H3K79 methylation show increased sensitivity to gamma-irradiation and chromosomal instability.","method":"ChIP; H3K79 methylation analysis in human and murine leukemic cells; gamma-irradiation sensitivity assays; cytogenetic analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — mechanistic ChIP data in both human and murine cells, functional irradiation sensitivity assay, multiple orthogonal readouts","pmids":["19443658"],"is_preprint":false},{"year":2010,"finding":"MLLT10/AF10 and DOT1L interact with TCF4/β-catenin in mouse intestinal crypts and are recruited to Wnt target gene loci in a β-catenin-dependent manner, resulting in H3K79 methylation over coding regions; MLLT10/AF10-DOT1L are essential and largely dedicated activators of Wnt-dependent transcription required for intestinal homeostasis.","method":"Proteomics (affinity purification/MS); co-immunoprecipitation; ChIP-seq; siRNA knockdown with expression arrays; zebrafish morpholino knockdown; apc-mutant zebrafish rescue experiments","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal approaches (proteomics, ChIP, knockdown, in vivo zebrafish genetics), strong mechanistic evidence","pmids":["21103407"],"is_preprint":false},{"year":2011,"finding":"The clathrin-binding domain (C-terminal 248 aa of CALM) combined with the octapeptide motif-leucine zipper (OM-LZ) domain of AF10 is sufficient to induce AML in mice and recapitulates Hoxa cluster upregulation; structure-function analysis defines these two domains as the minimal oncogenic unit of CALM-AF10.","method":"Domain-deletion mutagenesis; retroviral transduction; colony-forming/serial replating assays; in vivo mouse leukemia model; gene expression analysis","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 1-2 — rigorous structure-function study with multiple deletion mutants tested in vitro and in vivo","pmids":["21681188"],"is_preprint":false},{"year":2011,"finding":"In leukemia cells, full-length CALM-AF10 localizes to the nucleus with no consistent effect on growth factor endocytosis; CALM-AF10 suppresses H3K79 methylation regardless of clathrin binding; CALM-AF10 has a propensity to homo-oligomerize as demonstrated by FRET analysis, suggesting the clathrin-binding domain provides dimerization rather than endocytic disruption.","method":"Fluorescence resonance energy transfer (FRET); subcellular localization analysis; H3K79 methylation assay; endocytosis assays in leukemia cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — FRET for oligomerization, direct localization and methylation assays; single lab but multiple methods","pmids":["21706055"],"is_preprint":false},{"year":2012,"finding":"MLL-AF10 and CALM-AF10-mediated leukemic transformation is dependent on the H3K79 methyltransferase DOT1L; conditional genetic knockout of Dot1l abolishes in vitro transformation and in vivo leukemia initiation/maintenance; pharmacological inhibition of DOT1L (EPZ004777) suppresses Hoxa cluster and Meis1 expression and selectively impairs proliferation of AF10-fusion leukemia cells.","method":"Conditional knockout mouse model (Dot1l flox); in vitro bone marrow transformation; in vivo leukemia transplantation; pharmacological inhibition with EPZ004777; gene expression analysis","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 1-2 — genetic and pharmacological validation, in vitro and in vivo, replicated across two fusion types","pmids":["23138183"],"is_preprint":false},{"year":2012,"finding":"The PHD1-PHD2 module of ZFP-1 (C. elegans AF10 ortholog) is essential for viability; the first PHD finger mediates preferential binding to H3K4-methylated histone H3 tails; ZFP-1 genome-wide localization peaks overlap with H3K4 methylation-enriched promoters of actively expressed genes, and H3K4 methylation is required for ZFP-1 promoter localization in embryos.","method":"Genetic deletion analysis in C. elegans; biochemical histone peptide binding assays; ChIP-seq/genomic localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — genetic essentiality, biochemical binding assay for H3K4me, genome-wide localization in ortholog","pmids":["23263989"],"is_preprint":false},{"year":2013,"finding":"The C. elegans AF10 ortholog ZFP-1 and its interacting partner DOT-1.1 globally reduce RNA Pol II transcription on essential widely expressed genes; the ZFP-1/DOT-1.1 complex promotes Pol II pausing and is associated with increased H3K79 methylation and decreased H2B monoubiquitination at highly expressed genes, constituting a negative feedback mechanism on transcription.","method":"Genomic approaches (ChIP-seq, RNA-seq); biochemical co-immunoprecipitation; genetic knockdown of ZFP-1 and DOT-1.1 in C. elegans","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide and biochemical approaches combined with genetic validation; mechanistically dissects AF10 ortholog function in transcription elongation","pmids":["23806335"],"is_preprint":false},{"year":2013,"finding":"CALM contains a CRM1-dependent nuclear export signal (NES) that mediates cytoplasmic localization of CALM-AF10 and is necessary for CALM-AF10-dependent transformation; NES motifs from heterologous proteins fused to AF10 are sufficient to immortalize hematopoietic progenitors; the CALM NES is essential for Hoxa gene upregulation and aberrant H3K79 methylation, possibly by mislocalizing DOT1L.","method":"Mutagenesis of NES; retroviral transduction/bone marrow immortalization assays; Leptomycin B inhibition; gene expression analysis; H3K79 methylation analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — NES mutagenesis, heterologous NES substitution, pharmacological inhibition with mechanistic readouts","pmids":["23487024"],"is_preprint":false},{"year":2014,"finding":"CRM1 (nuclear export receptor) localizes to HOXA gene loci where it recruits CALM-AF10 via the CALM NES, leading to transcriptional and epigenetic activation of HOXA genes; genetic and pharmacological inhibition of the CALM-CRM1 interaction prevents CALM-AF10 enrichment at HOXA chromatin and immediately abolishes HOXA transcription.","method":"ChIP; CRM1 inhibition (Leptomycin B); genetic disruption of NES; gene expression analysis","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — ChIP demonstrates CRM1 at HOXA loci, NES mutagenesis and pharmacological inhibition confirm mechanism with multiple readouts","pmids":["25027513"],"is_preprint":false},{"year":2014,"finding":"The AF10 coiled-coil/leucine zipper domain interacts with GAS41 at a defined interaction site; a peptide inhibitor selected by phage display against the AF10 coiled-coil domain inhibits Hoxa gene expression when deployed in histiocytic lymphoma cells.","method":"Synthetic peptide mapping; phage display selection; CD spectroscopy; phage ELISA; mammalian cell transfection with inhibitory peptide; Hoxa gene expression analysis","journal":"Journal of peptide science","confidence":"Medium","confidence_rationale":"Tier 2-3 — interaction site mapping confirmed biochemically; functional inhibitory peptide validated in cells","pmids":["24692230"],"is_preprint":false},{"year":2014,"finding":"Nuclear export signal (NES) within CALM is necessary and sufficient for cytoplasmic localization of CALM-AF10; NES mutations eliminate the capacity of CALM-AF10 to immortalize bone marrow cells in vitro and to induce AML in mice; fusion of AF10 with the minimal NES is sufficient to immortalize cells and induce leukemia.","method":"NES mutagenesis; subcellular localization analysis; bone marrow immortalization assays; mouse leukemia model","journal":"Cancer science","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis plus in vitro and in vivo functional validation; minimal NES sufficiency established","pmids":["24397609"],"is_preprint":false},{"year":2015,"finding":"The PZP (PHD finger-Zn knuckle-PHD finger) domain of AF10 folds into a single module that recognizes amino acids 22-27 of histone H3 and specifically accommodates unmodified H3K27 (modification of H3K27 abrogates binding); crystal structure reveals H3 binding triggers rearrangement of the PZP module forming an H3(22-27)-accommodating channel with an unmodified H3K27 side chain encased in a compact hydrogen-bond acceptor-lined cage; in cells, PZP-H3 interaction is required for H3K79 dimethylation, DOT1L-target gene expression, and proliferation of DOT1L-addicted leukemic cells.","method":"Crystal structure determination; biochemical binding assays; mutagenesis of PZP domain; H3K79 methylation analysis in cells; gene expression analysis; cell proliferation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation by mutagenesis, biochemical binding assays, and cellular readouts; multiple orthogonal methods","pmids":["26439302"],"is_preprint":false},{"year":2017,"finding":"Mllt10 knockout mice exhibit midline facial cleft due to reduced proliferation of mesenchyme in developing nasal processes; H3K79 methylation is significantly decreased in nasal processes of Mllt10-KO embryos; AF10-dependent H3K79 methylation directly regulates AP2α expression in nasal processes, and suppression of H3K79 methylation fully mimics the Mllt10-KO phenotype.","method":"Mllt10 knockout mouse; phenotypic analysis; H3K79 methylation assay; gene expression analysis; ChIP for H3K79me at AP2α locus; pharmacological H3K79me suppression","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with specific phenotypic readout, ChIP linking AF10 to H3K79me at a specific target gene, pharmacological recapitulation of phenotype","pmids":["28931923"],"is_preprint":false},{"year":2018,"finding":"Crystal structures of apo AF10 OM-LZ domain and its complex with the coiled-coil domain of DOT1L reveal the molecular interface of AF10-DOT1L interaction; zinc stabilizes the DOT1L-AF10 complex; mutagenesis of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation.","method":"X-ray crystallography (apo and complex structures); mutagenesis of interface residues; leukemic transformation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus functional transformation assay; rigorous mechanistic study","pmids":["29563185"],"is_preprint":false},{"year":2021,"finding":"AF10 (MLLT10) prevents somatic cell reprogramming by regulating DOT1L-mediated H3K79 methylation; proximity-based labeling identifies AF10 as a DOT1L interactor in somatic cells; AF10 suppression increases reprogramming efficiency; re-expression of wild-type AF10 but not a DOT1L binding-impaired mutant rescues H3K79 methylation and reduces reprogramming.","method":"Proximity-based labeling (BioID) proteomics; RNA interference; CRISPR/Cas9 knockout; reprogramming efficiency assays; H3K79 methylation analysis; transcriptomics","journal":"Epigenetics & chromatin","confidence":"High","confidence_rationale":"Tier 1-2 — DOT1L-binding mutant rescue experiment directly links AF10's H3K79 regulation to reprogramming barrier; multiple orthogonal methods","pmids":["34215314"],"is_preprint":false},{"year":2021,"finding":"The PZP domain of AF10, which binds nucleosomes through multivalent contacts with the histone H3 tail and DNA, is consistently impaired or deleted in leukemogenic AF10 translocations; incorporation of functional AF10 PZP into CALM-AF10 prevents transforming activity in vitro and in vivo, promotes nuclear localization of CALM-AF10, and is required for chromatin association; AF10 PZP discriminates against the repressive H3K27me3 mark.","method":"Crystallography; biochemical binding assays with nucleosome core particles; mutagenesis; bone marrow transformation assays in vitro and in vivo (mouse models); ChIP; subcellular fractionation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure, biochemical nucleosome binding, mutagenesis, and both in vitro and in vivo functional validation; multiple orthogonal methods","pmids":["34226546"],"is_preprint":false},{"year":2021,"finding":"AF10 fusions (CALM-AF10 and MLL-AF10) activate a JAK/STAT-mediated inflammatory signaling cascade through direct recruitment of JAK1 kinase; genetic Jak1 deletion or pharmacological JAK/STAT inhibition elicits potent anti-oncogenic effects in mouse and human models of AF10 fusion AML.","method":"Inducible mouse AML models; transcriptomic, epigenomic, proteomic, and functional genomic approaches; co-immunoprecipitation for JAK1 recruitment; genetic Jak1 deletion; pharmacological JAK inhibition","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — comprehensive multi-omic characterization plus genetic and pharmacological validation of JAK1 as direct AF10 interactor and functional target","pmids":["33690798"],"is_preprint":false},{"year":2021,"finding":"Tip60 histone acetyltransferase is recruited by MLL-AF10 to the Hoxa9 locus where it acetylates H2A.Z to promote Hoxa9 gene expression; conditional deletion of Tip60 prevents development of MLL-AF10 leukemia.","method":"Co-immunoprecipitation (Tip60 recruitment by MLL-AF10); ChIP (Tip60 and H2A.Z acetylation at Hoxa9); conditional Tip60 knockout; leukemia development assay","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — ChIP-based mechanism at specific locus, conditional KO with leukemia phenotype, co-IP confirming recruitment","pmids":["33967269"],"is_preprint":false},{"year":2023,"finding":"DOT1L associates with MLLT10 (AF10) in testis; both proteins co-localize to sex chromatin in meiotic and post-meiotic germ cells in an inter-dependent manner; loss of either DOT1L or MLLT10 leads to reduced testis weight, decreased sperm count, male subfertility, and substantial retention of histones in epididymal sperm, demonstrating that H3K79 methylation promoted by the DOT1L-MLLT10 complex is essential for histone-to-protamine transition during spermiogenesis.","method":"Mouse knockout models (DOT1L and MLLT10); co-immunoprecipitation; immunofluorescence co-localization; H3K79me2 analysis; sperm histone retention assay","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — dual KO with specific phenotype, co-IP and co-localization confirming complex, direct H3K79me2 measurement; multiple orthogonal methods","pmids":["37082953"],"is_preprint":false},{"year":2023,"finding":"AF10 (MLLT10) controls patterning of H3K79me2/3 methylation at gene bodies; AF10 deletion evicts H3K79me2/3 and redistributes H3K79me1 to transcription start sites; AF10 loss also redistributes RNA Polymerase II to a pluripotent pattern at highly expressed housekeeping genes, facilitating iPSC formation without steady-state transcriptional changes. This identifies a specific function of H3K79me2/3 at gene bodies in reinforcing cell identity.","method":"Genetic AF10 deletion; chemical DOT1L inhibition; ChIP-seq for H3K79me1/2/3 and RNA Pol II; iPSC reprogramming efficiency assays","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — genetic and chemical approaches combined with genome-wide ChIP-seq; mechanistically dissects how AF10 patterns H3K79me orders","pmids":["37995701"],"is_preprint":false}],"current_model":"MLLT10/AF10 is a transcriptional co-regulator that functions as an essential cofactor for the H3K79 methyltransferase DOT1L, recruiting it to gene bodies (including HOXA cluster genes and Wnt targets) through direct protein-protein interaction mediated by the AF10 octapeptide motif-leucine zipper (OM-LZ) domain, while its N-terminal PZP domain reads unmodified H3K27 on nucleosomes to direct chromatin targeting; in leukemic translocations, the PZP domain is lost and the OM-LZ is fused to MLL or CALM, misrecruiting DOT1L to HOXA loci (driven partly by CALM's CRM1-dependent nuclear export signal and cytoplasmic-nuclear shuttling), causing H3K79 hypermethylation and HOXA gene upregulation that drives transformation, while additionally recruiting JAK1 kinase to activate JAK/STAT inflammatory signaling; in normal physiology, AF10-DOT1L deposits H3K79me2/3 at gene bodies to maintain somatic cell identity, regulate Wnt target gene transcription in intestinal crypts, regulate AP2α expression in craniofacial development, and promote histone-to-protamine transition during spermiogenesis."},"narrative":{"teleology":[{"year":1995,"claim":"Identification of AF10's domain architecture — a zinc-finger/PHD module and leucine zipper — in leukemia translocations established that the leucine zipper is consistently retained in MLL-AF10 fusions, pointing to it as functionally critical for oncogenesis.","evidence":"Sequence analysis and RT-PCR characterization of multiple t(10;11) leukemia patient samples","pmids":["7568208","7662954"],"confidence":"Medium","gaps":["No direct functional test of leucine zipper in transformation","DNA-binding activity of PHD finger predicted but not biochemically validated"]},{"year":1996,"claim":"Discovery of the CALM-AF10 fusion in t(10;11)(p13;q14) revealed a second translocation partner for AF10 and introduced the clathrin-assembly protein CALM into leukemia biology.","evidence":"Positional cloning from U937 cells identifying the CALM-AF10 fusion gene","pmids":["8643484"],"confidence":"High","gaps":["Mechanism by which CALM contributes to transformation unknown","Whether clathrin-binding function is relevant to leukemogenesis unclear"]},{"year":2000,"claim":"Biochemical reconstitution showed the PHD/LAP domain mediates AF10 homo-oligomerization and that AF10 binds DNA via an AT-hook motif, establishing AF10 as a chromatin-associated protein.","evidence":"Recombinant protein oligomerization assays, DNA binding assays, and subcellular fractionation","pmids":["10860745"],"confidence":"High","gaps":["Physiological chromatin targets unknown","Relevance of AT-hook DNA binding to gene regulation untested"]},{"year":2001,"claim":"Identification of GAS41 and INI1/SNF5 as AF10 leucine-zipper interactors linked AF10 to SWI/SNF chromatin remodeling, while Drosophila AF10 (Alhambra) was shown to interact with HP1 and function in heterochromatin-dependent silencing, establishing AF10 as a chromatin regulatory factor across species.","evidence":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells; genetic suppressor analysis of position-effect variegation and HP1 pull-down in Drosophila","pmids":["11756182","11266362"],"confidence":"High","gaps":["Whether GAS41-AF10 interaction is relevant in leukemia unclear","Mechanism of HP1 interaction in mammalian AF10 not tested"]},{"year":2002,"claim":"Structure-function analysis proved the AF10 leucine zipper is necessary and sufficient for MLL-AF10-mediated leukemic transformation, directly linking a specific AF10 domain to oncogenic activity.","evidence":"Retroviral transduction of murine myeloid progenitors with deletion mutants; serial replating and in vivo leukemia induction","pmids":["11986236"],"confidence":"High","gaps":["The leucine zipper's binding partner mediating transformation not yet identified","Downstream transcriptional targets not defined"]},{"year":2003,"claim":"Drosophila experiments revealed that the AF10 PHD domain autoinhibits the transcriptional activation capacity of the leucine zipper, explaining why MLL-AF10 (which lacks the PHD) derepresses Polycomb targets — establishing an intramolecular regulatory mechanism.","evidence":"Overexpression of isolated AF10 domains versus full-length protein in Drosophila PRE reporter assays","pmids":["12482966"],"confidence":"Medium","gaps":["Autoinhibition not demonstrated with purified mammalian AF10","Polycomb group derepression mechanism in mammalian leukemia not confirmed"]},{"year":2006,"claim":"The pivotal discovery that DOT1L (H3K79 methyltransferase) is recruited by AF10 and is required for CALM-AF10-mediated Hoxa5 upregulation and leukemogenesis established the AF10-DOT1L axis as the central oncogenic mechanism in AF10-rearranged leukemia.","evidence":"Co-immunoprecipitation, ChIP for H3K79me at Hoxa5, shRNA knockdown of DOT1L, bone marrow transformation assays","pmids":["16921363"],"confidence":"High","gaps":["Direct binding interface between AF10 and DOT1L not structurally characterized","Whether DOT1L recruitment is the sole mechanism of transformation unknown"]},{"year":2009,"claim":"CALM-AF10 was found to globally reduce H3K79 methylation while locally hypermethylating Hoxa5, revealing that the fusion disrupts normal AF10-DOT1L chromatin distribution and causes genomic instability through global H3K79me depletion.","evidence":"ChIP and H3K79me analysis in human and murine leukemic cells; gamma-irradiation sensitivity and cytogenetic assays","pmids":["19443658"],"confidence":"High","gaps":["Mechanism of selective local hypermethylation versus global hypomethylation not resolved","Whether genomic instability contributes to disease progression independently unclear"]},{"year":2010,"claim":"AF10 and DOT1L were shown to be recruited to Wnt target genes by TCF4/β-catenin in intestinal crypts, depositing H3K79me over coding regions, thereby establishing the first physiological role of AF10 in normal tissue homeostasis beyond leukemia.","evidence":"Affinity purification/MS proteomics, co-IP, ChIP-seq, siRNA knockdown with expression arrays, zebrafish morpholino and apc-mutant rescue","pmids":["21103407"],"confidence":"High","gaps":["Whether AF10-DOT1L has Wnt-independent roles in the intestine not addressed","Tissue-specific regulation of AF10-TCF4 interaction unclear"]},{"year":2011,"claim":"Minimal-domain analyses of CALM-AF10 defined the CALM clathrin-binding domain plus AF10 OM-LZ as the minimal oncogenic unit, while FRET showed CALM-AF10 homo-oligomerizes, suggesting the clathrin domain contributes via dimerization rather than endocytic disruption.","evidence":"Domain-deletion mutagenesis with in vitro and in vivo transformation assays; FRET analysis of oligomerization","pmids":["21681188","21706055"],"confidence":"High","gaps":["Structural basis of CALM-mediated oligomerization not resolved","Whether oligomerization is required for DOT1L recruitment unknown"]},{"year":2012,"claim":"C. elegans ortholog studies revealed that AF10 (ZFP-1) PHD1 binds H3K4-methylated tails and localizes to active promoters genome-wide, identifying a conserved chromatin-reading function distinct from the H3K27-recognition later found for the PZP domain.","evidence":"Genetic deletion, histone peptide binding assays, and ChIP-seq in C. elegans","pmids":["23263989"],"confidence":"High","gaps":["Whether mammalian AF10 PZP also reads H3K4me not tested","Potential divergence between nematode and mammalian AF10 chromatin reading"]},{"year":2012,"claim":"Genetic knockout and pharmacological inhibition of DOT1L definitively established that H3K79 methyltransferase activity is required for both MLL-AF10 and CALM-AF10 leukemic transformation, validating DOT1L as a therapeutic target.","evidence":"Conditional Dot1l knockout mouse; EPZ004777 inhibitor; in vitro transformation and in vivo leukemia assays; Hoxa/Meis1 expression analysis","pmids":["23138183"],"confidence":"High","gaps":["Whether DOT1L inhibition has sufficient therapeutic window in patients unknown","Non-H3K79me mechanisms of AF10 fusion oncogenesis not excluded"]},{"year":2013,"claim":"The CALM NES (CRM1-dependent nuclear export signal) was shown to be necessary and sufficient for CALM-AF10 leukemogenesis, with CRM1 recruiting the fusion to HOXA chromatin — resolving a long-standing question of why a clathrin-adaptor protein drives nuclear oncogenesis.","evidence":"NES mutagenesis, heterologous NES substitution, Leptomycin B inhibition, ChIP showing CRM1 at HOXA loci, bone marrow transformation and mouse leukemia models","pmids":["23487024","25027513","24397609"],"confidence":"High","gaps":["How CRM1 specifically targets HOXA loci mechanistically unclear","Whether other NES-containing fusions can similarly transform unclear"]},{"year":2013,"claim":"Genome-wide studies in C. elegans showed that the ZFP-1/DOT-1.1 complex promotes RNA Pol II pausing at highly expressed genes, constituting a negative transcriptional feedback mechanism — providing the first evidence that AF10-DOT1L restrains rather than simply activates transcription.","evidence":"ChIP-seq, RNA-seq, and genetic knockdown in C. elegans","pmids":["23806335"],"confidence":"High","gaps":["Whether Pol II pausing function is conserved in mammalian AF10-DOT1L not tested","Mechanism linking H3K79me to pausing not defined"]},{"year":2015,"claim":"Crystal structure of the AF10 PZP domain bound to H3 revealed it recognizes unmodified H3K27 through a hydrogen-bond cage, directly explaining why H3K27 methylation antagonizes AF10 chromatin targeting and why PZP loss in translocations deregulates DOT1L.","evidence":"X-ray crystallography, biochemical binding assays with modified histone peptides, mutagenesis, cellular H3K79me and proliferation assays","pmids":["26439302"],"confidence":"High","gaps":["How PZP-H3K27 reading is coordinated with DOT1L catalysis not structurally resolved","Whether PZP also reads nucleosomal DNA contacts not addressed in this study"]},{"year":2017,"claim":"Mllt10 knockout mice exhibited midline facial cleft with reduced H3K79me at the AP2α locus, establishing AF10 as essential for craniofacial development through DOT1L-dependent regulation of specific developmental genes.","evidence":"Mllt10 knockout mouse; H3K79me ChIP at AP2α; pharmacological H3K79me suppression recapitulating phenotype","pmids":["28931923"],"confidence":"High","gaps":["Whether other developmental targets beyond AP2α are regulated by AF10 in facial development unknown","Human craniofacial disease association not established"]},{"year":2018,"claim":"Crystal structures of the AF10 OM-LZ domain alone and in complex with DOT1L's coiled-coil defined the molecular interface and showed zinc stabilizes the complex; interface mutations abolished leukemic transformation, providing a structural blueprint for therapeutic disruption.","evidence":"X-ray crystallography of apo and complex; interface mutagenesis; leukemic transformation assays","pmids":["29563185"],"confidence":"High","gaps":["No small-molecule inhibitor of the AF10-DOT1L interface developed","Whether interface disruption affects normal AF10 physiology not assessed"]},{"year":2021,"claim":"Multiple studies converged to show that AF10 PZP binds nucleosomes through multivalent H3-tail and DNA contacts, that PZP incorporation into CALM-AF10 suppresses transformation, that AF10 fusions recruit JAK1 to activate JAK/STAT signaling as a parallel oncogenic mechanism, and that Tip60 is recruited by MLL-AF10 to acetylate H2A.Z at Hoxa9 — revealing transformation requires multiple epigenetic and signaling axes.","evidence":"Crystallography and nucleosome binding; in vivo mouse transformation with PZP-containing constructs; multi-omic profiling with genetic Jak1 deletion and JAK inhibition; co-IP and conditional Tip60 knockout","pmids":["34226546","33690798","33967269"],"confidence":"High","gaps":["Relative contribution of JAK/STAT versus DOT1L axis to transformation not quantified","Whether Tip60 recruitment is specific to MLL-AF10 or shared with CALM-AF10 unclear","Structural basis of JAK1 recruitment by AF10 not determined"]},{"year":2021,"claim":"AF10 was identified as a DOT1L cofactor that maintains the somatic cell epigenetic barrier to reprogramming: AF10 loss facilitates iPSC formation, and rescue requires intact DOT1L-binding capacity, linking AF10-H3K79me to cell identity maintenance.","evidence":"BioID proximity labeling, RNAi, CRISPR knockout, DOT1L-binding-impaired mutant rescue, reprogramming efficiency assays","pmids":["34215314"],"confidence":"High","gaps":["Which specific loci lose H3K79me to permit reprogramming not mapped genome-wide","Whether AF10 has DOT1L-independent roles in cell identity not excluded"]},{"year":2023,"claim":"AF10 deletion evicts H3K79me2/3 from gene bodies and redistributes H3K79me1 to TSSs and Pol II to a pluripotent pattern without altering steady-state transcription, defining a specific gene-body H3K79me2/3 function in reinforcing cell identity; separately, DOT1L-MLLT10 was shown essential for spermiogenesis through histone-to-protamine transition.","evidence":"Genetic AF10 deletion plus ChIP-seq for H3K79me1/2/3 and Pol II; DOT1L and MLLT10 knockout mice with sperm histone retention assays and co-IP/co-localization in testis","pmids":["37995701","37082953"],"confidence":"High","gaps":["How H3K79me2/3 at gene bodies mechanistically prevents Pol II redistribution unknown","Whether the spermiogenesis phenotype involves the same PZP-dependent chromatin reading as somatic cells not tested"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of how PZP nucleosome reading is coordinated with OM-LZ-mediated DOT1L recruitment within the full-length AF10-DOT1L complex on chromatin; how H3K79me2/3 at gene bodies mechanistically reinforces somatic Pol II distribution; the relative therapeutic tractability of disrupting the AF10-DOT1L interface versus JAK/STAT inhibition in AF10-rearranged leukemia; and whether AF10 has DOT1L-independent functions in mammalian cells.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length AF10-DOT1L-nucleosome structural model exists","Mechanism by which gene-body H3K79me2/3 controls Pol II distribution remains undefined","Therapeutic targeting of AF10-DOT1L interface not achieved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[24,28,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,14,17,27,32]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,8,12,14,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,10,28]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[24,28,31,32]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,13,17,24,26,27,32]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,14,19,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,29]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[25,31]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,9,15,17,20,21,23,29]}],"complexes":["DOT1L complex","TCF4/β-catenin transcriptional complex"],"partners":["DOT1L","GAS41","PICALM","KMT2A","JAK1","KAT5","IKZF1","CTNNB1"],"other_free_text":[]},"mechanistic_narrative":"MLLT10 (AF10) is a chromatin reader and transcriptional co-regulator that directs the H3K79 methyltransferase DOT1L to gene bodies, thereby patterning H3K79me2/3 to maintain somatic cell identity, regulate Wnt target gene transcription in intestinal crypts, control craniofacial morphogenesis, and promote histone-to-protamine transition during spermiogenesis [PMID:21103407, PMID:28931923, PMID:37082953, PMID:37995701]. Its N-terminal PZP domain binds nucleosomes by recognizing unmodified H3K27 and engaging DNA, while its C-terminal OM-LZ domain directly contacts the DOT1L coiled-coil, with crystal structures defining both interfaces; the PZP domain acts as an autoinhibitory module that restrains the transcriptional activation capacity of the OM-LZ [PMID:26439302, PMID:34226546, PMID:29563185, PMID:12482966]. In recurrent leukemia-associated translocations (MLL-AF10 and CALM-AF10), the PZP domain is lost and the OM-LZ is retained, causing DOT1L misrecruitment, H3K79 hypermethylation at HOXA loci, HOXA/MEIS1 upregulation, and JAK1-mediated JAK/STAT inflammatory signaling that together drive myeloid transformation [PMID:16921363, PMID:23138183, PMID:33690798, PMID:25027513]. AF10 also bridges DOT1L to additional chromatin regulators including GAS41 (linking to SWI/SNF remodeling), Ikaros, and the TCF4/β-catenin complex, and its deletion redistributes RNA Polymerase II to a pluripotent pattern, establishing AF10-dependent H3K79me2/3 as a barrier to somatic cell reprogramming [PMID:11756182, PMID:18037964, PMID:21103407, PMID:34215314, PMID:37995701]."},"prefetch_data":{"uniprot":{"accession":"P55197","full_name":"Protein AF-10","aliases":["ALL1-fused gene from chromosome 10 protein"],"length_aa":1068,"mass_kda":113.3,"function":"Probably involved in transcriptional regulation. In vitro or as fusion protein with KMT2A/MLL1 has transactivation activity. Binds to cruciform DNA. In cells, binding to unmodified histone H3 regulates DOT1L functions including histone H3 'Lys-79' dimethylation (H3K79me2) and gene activation (PubMed:26439302)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P55197/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MLLT10","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MLLT10","total_profiled":1310},"omim":[{"mim_id":"612708","title":"RANBP2-LIKE AND GRIP DOMAIN-CONTAINING PROTEIN 5; RGPD5","url":"https://www.omim.org/entry/612708"},{"mim_id":"608757","title":"CLEAVAGE FACTOR POLYNUCLEOTIDE KINASE SUBUNIT 1; CLP1","url":"https://www.omim.org/entry/608757"},{"mim_id":"607375","title":"DOT1-LIKE; DOT1L","url":"https://www.omim.org/entry/607375"},{"mim_id":"607174","title":"MENINGIOMA, FAMILIAL, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607174"},{"mim_id":"602409","title":"MLLT10 HISTONE LYSINE METHYLTRANSFERASE DOT1L COFACTOR; MLLT10","url":"https://www.omim.org/entry/602409"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":86.9}],"url":"https://www.proteinatlas.org/search/MLLT10"},"hgnc":{"alias_symbol":["AF10"],"prev_symbol":[]},"alphafold":{"accession":"P55197","domains":[{"cath_id":"3.30.40.10","chopping":"40-208","consensus_level":"medium","plddt":92.4282,"start":40,"end":208}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55197","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55197-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55197-F1-predicted_aligned_error_v6.png","plddt_mean":50.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MLLT10","jax_strain_url":"https://www.jax.org/strain/search?query=MLLT10"},"sequence":{"accession":"P55197","fasta_url":"https://rest.uniprot.org/uniprotkb/P55197.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55197/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55197"}},"corpus_meta":[{"pmid":"8643484","id":"PMC_8643484","title":"The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8643484","citation_count":267,"is_preprint":false},{"pmid":"16921363","id":"PMC_16921363","title":"Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L.","date":"2006","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16921363","citation_count":147,"is_preprint":false},{"pmid":"7568208","id":"PMC_7568208","title":"The leukemia-associated-protein (LAP) domain, a cysteine-rich motif, is present in a wide range of proteins, including MLL, AF10, and MLLT6 proteins.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7568208","citation_count":137,"is_preprint":false},{"pmid":"7662954","id":"PMC_7662954","title":"The t(10;11) translocation in acute myeloid leukemia (M5) consistently fuses the leucine zipper motif of AF10 onto the HRX gene.","date":"1995","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/7662954","citation_count":115,"is_preprint":false},{"pmid":"12676784","id":"PMC_12676784","title":"CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCRgammadelta lineage.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12676784","citation_count":114,"is_preprint":false},{"pmid":"23138183","id":"PMC_23138183","title":"Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l.","date":"2012","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/23138183","citation_count":114,"is_preprint":false},{"pmid":"11986236","id":"PMC_11986236","title":"The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11986236","citation_count":112,"is_preprint":false},{"pmid":"17097559","id":"PMC_17097559","title":"Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia.","date":"2006","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/17097559","citation_count":98,"is_preprint":false},{"pmid":"7671224","id":"PMC_7671224","title":"Breakpoint heterogeneity in t(10;11) translocation in AML-M4/M5 resulting in fusion of AF10 and MLL is resolved by fluorescent in situ hybridization analysis.","date":"1995","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7671224","citation_count":79,"is_preprint":false},{"pmid":"11756182","id":"PMC_11756182","title":"The MLL fusion partner AF10 binds GAS41, a protein that interacts with the human SWI/SNF complex.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11756182","citation_count":76,"is_preprint":false},{"pmid":"21103407","id":"PMC_21103407","title":"The leukemia-associated Mllt10/Af10-Dot1l are Tcf4/β-catenin coactivators essential for intestinal homeostasis.","date":"2010","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/21103407","citation_count":75,"is_preprint":false},{"pmid":"8388418","id":"PMC_8388418","title":"Recombinant IL-6 activates p42 and p44 mitogen-activated protein kinases in the IL-6 responsive B cell line, AF-10.","date":"1993","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8388418","citation_count":72,"is_preprint":false},{"pmid":"10637482","id":"PMC_10637482","title":"Molecular analysis of the CALM/AF10 fusion: identical rearrangements in acute myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma patients.","date":"2000","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/10637482","citation_count":71,"is_preprint":false},{"pmid":"26439302","id":"PMC_26439302","title":"The PZP Domain of AF10 Senses Unmodified H3K27 to Regulate DOT1L-Mediated Methylation of H3K79.","date":"2015","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/26439302","citation_count":68,"is_preprint":false},{"pmid":"18094714","id":"PMC_18094714","title":"The role of CALM-AF10 gene fusion in acute leukemia.","date":"2007","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/18094714","citation_count":64,"is_preprint":false},{"pmid":"10860745","id":"PMC_10860745","title":"Biochemical analyses of the AF10 protein: the extended LAP/PHD-finger mediates oligomerisation.","date":"2000","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10860745","citation_count":64,"is_preprint":false},{"pmid":"17804713","id":"PMC_17804713","title":"Expression of a CALM-AF10 fusion gene leads to Hoxa cluster overexpression and acute leukemia in transgenic mice.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17804713","citation_count":59,"is_preprint":false},{"pmid":"23673860","id":"PMC_23673860","title":"New MLLT10 gene recombinations in pediatric T-acute lymphoblastic leukemia.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23673860","citation_count":55,"is_preprint":false},{"pmid":"10554802","id":"PMC_10554802","title":"Consistent detection of CALM-AF10 chimaeric transcripts in haematological malignancies with t(10;11)(p13;q14) and identification of novel transcripts.","date":"1999","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/10554802","citation_count":51,"is_preprint":false},{"pmid":"16491119","id":"PMC_16491119","title":"The novel CALM interactor CATS influences the subcellular localization of the leukemogenic fusion protein CALM/AF10.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16491119","citation_count":50,"is_preprint":false},{"pmid":"19443658","id":"PMC_19443658","title":"Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10-positive leukemias.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19443658","citation_count":50,"is_preprint":false},{"pmid":"23806335","id":"PMC_23806335","title":"The ZFP-1(AF10)/DOT-1 complex opposes H2B ubiquitination to reduce Pol II transcription.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/23806335","citation_count":45,"is_preprint":false},{"pmid":"22871473","id":"PMC_22871473","title":"PICALM-MLLT10 acute myeloid leukemia: a French cohort of 18 patients.","date":"2012","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/22871473","citation_count":45,"is_preprint":false},{"pmid":"10221337","id":"PMC_10221337","title":"Mixed-lineage leukemia with t(10;11)(p13;q21): an analysis of AF10-CALM and CALM-AF10 fusion mRNAs and clinical features.","date":"1999","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10221337","citation_count":42,"is_preprint":false},{"pmid":"11423977","id":"PMC_11423977","title":"The synovial sarcoma associated protein SYT interacts with the acute leukemia associated protein AF10.","date":"2001","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11423977","citation_count":41,"is_preprint":false},{"pmid":"19383357","id":"PMC_19383357","title":"The CALM and CALM/AF10 interactor CATS is a marker for proliferation.","date":"2008","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19383357","citation_count":38,"is_preprint":false},{"pmid":"25027513","id":"PMC_25027513","title":"A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias.","date":"2014","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/25027513","citation_count":38,"is_preprint":false},{"pmid":"22064352","id":"PMC_22064352","title":"CALM/AF10-positive leukemias show upregulation of genes involved in chromatin assembly and DNA repair processes and of genes adjacent to the breakpoint at 10p12.","date":"2011","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/22064352","citation_count":38,"is_preprint":false},{"pmid":"21681188","id":"PMC_21681188","title":"The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice.","date":"2011","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/21681188","citation_count":32,"is_preprint":false},{"pmid":"18037964","id":"PMC_18037964","title":"The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18037964","citation_count":31,"is_preprint":false},{"pmid":"23487024","id":"PMC_23487024","title":"A CALM-derived nuclear export signal is essential for CALM-AF10-mediated leukemogenesis.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23487024","citation_count":31,"is_preprint":false},{"pmid":"8896421","id":"PMC_8896421","title":"AF10 is split by MLL and HEAB, a human homolog to a putative Caenorhabditis elegans ATP/GTP-binding protein in an invins(10;11)(p12;q23q12).","date":"1996","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/8896421","citation_count":30,"is_preprint":false},{"pmid":"23564351","id":"PMC_23564351","title":"Involvement of Gpr125 in the myeloid sarcoma formation induced by cooperating MLL/AF10(OM-LZ) and oncogenic KRAS in a mouse bone marrow transplantation model.","date":"2013","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23564351","citation_count":27,"is_preprint":false},{"pmid":"12482966","id":"PMC_12482966","title":"The leucine zipper motif of the Drosophila AF10 homologue can inhibit PRE-mediated repression: implications for leukemogenic activity of human MLL-AF10 fusions.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12482966","citation_count":27,"is_preprint":false},{"pmid":"30707474","id":"PMC_30707474","title":"Acute leukemias harboring KMT2A/MLLT10 fusion: a 10-year experience from a single genomics laboratory.","date":"2019","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30707474","citation_count":26,"is_preprint":false},{"pmid":"9737689","id":"PMC_9737689","title":"Alternative splicing in wild-type AF10 and CALM cDNAs and in AF10-CALM and CALM-AF10 fusion cDNAs produced by the t(10;11)(p13-14;q14-q21) suggests a potential role for truncated AF10 polypeptides.","date":"1998","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/9737689","citation_count":25,"is_preprint":false},{"pmid":"11477655","id":"PMC_11477655","title":"t(10;11)-acute leukemias with MLL-AF10 and MLL-ABI1 chimeric transcripts: specific expression patterns of ABI1 gene in leukemia and solid tumor cell lines.","date":"2001","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11477655","citation_count":24,"is_preprint":false},{"pmid":"20875875","id":"PMC_20875875","title":"Acute leukemia with PICALM-MLLT10 fusion gene: diagnostic and treatment struggle.","date":"2010","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/20875875","citation_count":23,"is_preprint":false},{"pmid":"11266362","id":"PMC_11266362","title":"The Drosophila homolog of the human AF10 is an HP1-interacting suppressor of position effect variegation.","date":"2001","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/11266362","citation_count":23,"is_preprint":false},{"pmid":"15135402","id":"PMC_15135402","title":"Purification and characterization of inulinase from Aspergillus niger AF10 expressed in Pichia pastoris.","date":"2004","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/15135402","citation_count":23,"is_preprint":false},{"pmid":"9878787","id":"PMC_9878787","title":"Expression pattern and cellular distribution of the murine homologue of AF10.","date":"1998","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9878787","citation_count":22,"is_preprint":false},{"pmid":"32765078","id":"PMC_32765078","title":"miR-331-3p Inhibits Tumor Cell Proliferation, Metastasis, Invasion by Targeting MLLT10 in Non-Small Cell Lung Cancer.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32765078","citation_count":21,"is_preprint":false},{"pmid":"29563185","id":"PMC_29563185","title":"Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis.","date":"2018","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/29563185","citation_count":21,"is_preprint":false},{"pmid":"12810254","id":"PMC_12810254","title":"Cytogenetics, fluorescence in situ hybridization, and reverse transcriptase polymerase chain reaction are necessary to clarify the various mechanisms leading to an MLL-AF10 fusion in acute myelocytic leukemia with 10;11 rearrangement.","date":"2003","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/12810254","citation_count":20,"is_preprint":false},{"pmid":"10602503","id":"PMC_10602503","title":"The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10602503","citation_count":19,"is_preprint":false},{"pmid":"20007546","id":"PMC_20007546","title":"Retroviral insertional mutagenesis identifies Zeb2 activation as a novel leukemogenic collaborating event in CALM-AF10 transgenic mice.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20007546","citation_count":18,"is_preprint":false},{"pmid":"32033330","id":"PMC_32033330","title":"The Association of the Copy Number Variation of the MLLT10 Gene with Growth Traits of Chinese Cattle.","date":"2020","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/32033330","citation_count":17,"is_preprint":false},{"pmid":"11135434","id":"PMC_11135434","title":"Molecular analysis of the genomic inversion and insertion of AF10 into MLL suggests a single-step event.","date":"2001","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11135434","citation_count":17,"is_preprint":false},{"pmid":"31022428","id":"PMC_31022428","title":"Acute myeloid leukemia driven by the CALM-AF10 fusion gene is dependent on BMI1.","date":"2019","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/31022428","citation_count":16,"is_preprint":false},{"pmid":"33967269","id":"PMC_33967269","title":"Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia.","date":"2021","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/33967269","citation_count":16,"is_preprint":false},{"pmid":"33690798","id":"PMC_33690798","title":"A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML.","date":"2021","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/33690798","citation_count":15,"is_preprint":false},{"pmid":"34226546","id":"PMC_34226546","title":"The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34226546","citation_count":14,"is_preprint":false},{"pmid":"9844603","id":"PMC_9844603","title":"Interstitial insertion of AF10 into the ALL1 gene in a case of infant acute lymphoblastic leukemia.","date":"1998","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/9844603","citation_count":14,"is_preprint":false},{"pmid":"17074587","id":"PMC_17074587","title":"A case of acute myelogenous leukemia with MLL-AF10 fusion caused by insertion of 5' MLL into 10p12, with concurrent 3' MLL deletion.","date":"2006","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17074587","citation_count":14,"is_preprint":false},{"pmid":"11165485","id":"PMC_11165485","title":"The Drosophila homolog of human AF10/AF17 leukemia fusion genes (Dalf) encodes a zinc finger/leucine zipper nuclear protein required in the nervous system for maintaining EVE expression and normal growth.","date":"2001","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/11165485","citation_count":14,"is_preprint":false},{"pmid":"34215314","id":"PMC_34215314","title":"AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation.","date":"2021","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/34215314","citation_count":13,"is_preprint":false},{"pmid":"21706055","id":"PMC_21706055","title":"The clathrin-binding domain of CALM-AF10 alters the phenotype of myeloid neoplasms in mice.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21706055","citation_count":13,"is_preprint":false},{"pmid":"15262427","id":"PMC_15262427","title":"MLL-MLLT10 fusion in acute monoblastic leukemia: variant complex rearrangements and 11q proximal breakpoint heterogeneity.","date":"2004","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/15262427","citation_count":13,"is_preprint":false},{"pmid":"11417476","id":"PMC_11417476","title":"Identification and molecular characterisation of a CALM-AF10 fusion in acute megakaryoblastic leukaemia.","date":"2001","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/11417476","citation_count":13,"is_preprint":false},{"pmid":"9305618","id":"PMC_9305618","title":"A novel MLL-AF10 fusion mRNA variant in a patient with acute myeloid leukemia detected by a new asymmetric reverse transcription PCR method.","date":"1997","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/9305618","citation_count":13,"is_preprint":false},{"pmid":"16111539","id":"PMC_16111539","title":"MLL-MLLT10 fusion gene in pediatric acute megakaryoblastic leukemia.","date":"2005","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/16111539","citation_count":12,"is_preprint":false},{"pmid":"23263989","id":"PMC_23263989","title":"The conserved PHD1-PHD2 domain of ZFP-1/AF10 is a discrete functional module essential for viability in Caenorhabditis elegans.","date":"2012","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23263989","citation_count":12,"is_preprint":false},{"pmid":"11911106","id":"PMC_11911106","title":"Incidence of MLL rearrangement in acute myeloid leukemia, and a CALM-AF10 fusion in M4 type acute myeloblastic leukemia.","date":"2002","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/11911106","citation_count":12,"is_preprint":false},{"pmid":"16213369","id":"PMC_16213369","title":"Cryptic MLL-AF10 fusion caused by insertion of duplicated 5' part of MLL into 10p12 in acute leukemia: a case report.","date":"2005","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/16213369","citation_count":12,"is_preprint":false},{"pmid":"35702670","id":"PMC_35702670","title":"Pleiotropic MLLT10 variation confers risk of meningioma and estrogen-mediated cancers.","date":"2022","source":"Neuro-oncology advances","url":"https://pubmed.ncbi.nlm.nih.gov/35702670","citation_count":11,"is_preprint":false},{"pmid":"28931923","id":"PMC_28931923","title":"Mllt10 knockout mouse model reveals critical role of Af10-dependent H3K79 methylation in midfacial development.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28931923","citation_count":11,"is_preprint":false},{"pmid":"11106826","id":"PMC_11106826","title":"CALM-AF10 fusion gene in leukemias: simple and inversion-associated translocation (10;11).","date":"2000","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/11106826","citation_count":11,"is_preprint":false},{"pmid":"11187895","id":"PMC_11187895","title":"Protean clinical manifestations in children with leukemias containing MLL-AF10 fusion.","date":"2000","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/11187895","citation_count":11,"is_preprint":false},{"pmid":"17868029","id":"PMC_17868029","title":"AF10-dependent transcription is enhanced by its interaction with FLRG.","date":"2007","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17868029","citation_count":11,"is_preprint":false},{"pmid":"38306602","id":"PMC_38306602","title":"Structural variants involving MLLT10 fusion are associated with adverse outcomes in pediatric acute myeloid leukemia.","date":"2024","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/38306602","citation_count":10,"is_preprint":false},{"pmid":"37743097","id":"PMC_37743097","title":"Treatment outcomes of childhood PICALM::MLLT10 acute leukaemias.","date":"2023","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/37743097","citation_count":10,"is_preprint":false},{"pmid":"30159143","id":"PMC_30159143","title":"Dysregulated transcriptional networks in KMT2A- and MLLT10-rearranged T-ALL.","date":"2018","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/30159143","citation_count":10,"is_preprint":false},{"pmid":"26686248","id":"PMC_26686248","title":"The target cell of transformation is distinct from the leukemia stem cell in murine CALM/AF10 leukemia models.","date":"2015","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/26686248","citation_count":10,"is_preprint":false},{"pmid":"20445327","id":"PMC_20445327","title":"Clathrin assembly lymphoid myeloid leukemia-AF10-positive acute leukemias: a report of 2 cases with a review of the literature.","date":"2010","source":"The Korean journal of laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20445327","citation_count":10,"is_preprint":false},{"pmid":"19711340","id":"PMC_19711340","title":"MLL/AF10(OM-LZ)-immortalized cells expressed cytokines and induced host cell proliferation in a mouse bone marrow transplantation model.","date":"2010","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19711340","citation_count":10,"is_preprint":false},{"pmid":"24397609","id":"PMC_24397609","title":"Nuclear export signal within CALM is necessary for CALM-AF10-induced leukemia.","date":"2014","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/24397609","citation_count":10,"is_preprint":false},{"pmid":"27859216","id":"PMC_27859216","title":"Cooperation of MLL/AF10(OM-LZ) with PTPN11 activating mutation induced monocytic leukemia with a shorter latency in a mouse bone marrow transplantation model.","date":"2016","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27859216","citation_count":10,"is_preprint":false},{"pmid":"12555219","id":"PMC_12555219","title":"Monocytic leukemia with CALM/AF10 rearrangement showing mediastinal emphysema.","date":"2003","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/12555219","citation_count":10,"is_preprint":false},{"pmid":"32569758","id":"PMC_32569758","title":"MLLT10 in benign and malignant hematopoiesis.","date":"2020","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/32569758","citation_count":9,"is_preprint":false},{"pmid":"37478796","id":"PMC_37478796","title":"Cryptic KMT2A/MLLT10 fusion detected by next-generation sequencing in a case of pediatric acute megakaryoblastic leukemia.","date":"2023","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37478796","citation_count":8,"is_preprint":false},{"pmid":"30227397","id":"PMC_30227397","title":"Mediastinal Myeloid Sarcoma with TP53 Mutation Preceding Acute Myeloid Leukemia with a PICALM-MLLT10 Fusion Gene.","date":"2018","source":"Acta haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/30227397","citation_count":8,"is_preprint":false},{"pmid":"32843425","id":"PMC_32843425","title":"Failure of tofacitinib to achieve an objective response in a DDX3X-MLLT10 T-lymphoblastic leukemia with activating JAK3 mutations.","date":"2020","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/32843425","citation_count":8,"is_preprint":false},{"pmid":"37082953","id":"PMC_37082953","title":"The DOT1L-MLLT10 complex regulates male fertility and promotes histone removal during spermiogenesis.","date":"2023","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/37082953","citation_count":7,"is_preprint":false},{"pmid":"24558261","id":"PMC_24558261","title":"Neuronal migration is regulated by endogenous RNAi and chromatin-binding factor ZFP-1/AF10 in Caenorhabditis elegans.","date":"2014","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24558261","citation_count":7,"is_preprint":false},{"pmid":"24692230","id":"PMC_24692230","title":"Characterization and inhibition of AF10-mediated interaction.","date":"2014","source":"Journal of peptide science : an official publication of the European Peptide Society","url":"https://pubmed.ncbi.nlm.nih.gov/24692230","citation_count":7,"is_preprint":false},{"pmid":"36158701","id":"PMC_36158701","title":"Broad genomic workup including optical genome mapping uncovers a DDX3X: MLLT10 gene fusion in acute myeloid leukemia.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36158701","citation_count":7,"is_preprint":false},{"pmid":"31739126","id":"PMC_31739126","title":"Molecular and phenotypic characterization of an early T-cell precursor acute lymphoblastic lymphoma harboring PICALM-MLLT10 fusion with aberrant expression of B-cell antigens.","date":"2019","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31739126","citation_count":7,"is_preprint":false},{"pmid":"8373639","id":"PMC_8373639","title":"Interferon-alpha and dexamethasone effect on AF10 myeloma cell line sialytransferase activity.","date":"1993","source":"Biochemical medicine and metabolic biology","url":"https://pubmed.ncbi.nlm.nih.gov/8373639","citation_count":6,"is_preprint":false},{"pmid":"38895061","id":"PMC_38895061","title":"PICALM::MLLT10 may indicate a new subgroup of acute leukemias with miscellaneous immunophenotype and poor initial treatment response but showing sensitivity to venetoclax.","date":"2024","source":"EJHaem","url":"https://pubmed.ncbi.nlm.nih.gov/38895061","citation_count":6,"is_preprint":false},{"pmid":"25193880","id":"PMC_25193880","title":"Effects of iron depletion on CALM-AF10 leukemias.","date":"2014","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/25193880","citation_count":6,"is_preprint":false},{"pmid":"9762409","id":"PMC_9762409","title":"A human B cell line AF10 expressing HIL-17.","date":"1998","source":"Biochemistry and molecular biology international","url":"https://pubmed.ncbi.nlm.nih.gov/9762409","citation_count":6,"is_preprint":false},{"pmid":"38036714","id":"PMC_38036714","title":"Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1.","date":"2023","source":"Journal of the Association for Research in Otolaryngology : JARO","url":"https://pubmed.ncbi.nlm.nih.gov/38036714","citation_count":5,"is_preprint":false},{"pmid":"38971327","id":"PMC_38971327","title":"Clinicopathologic features and outcomes of acute leukemia harboring PICALM::MLLT10 fusion.","date":"2024","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38971327","citation_count":5,"is_preprint":false},{"pmid":"36774707","id":"PMC_36774707","title":"Unexpected appearance of KMT2A::MLLT10 fusion transcript in acute myeloid leukemia with t(5;11)(q31;q23.3).","date":"2023","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36774707","citation_count":5,"is_preprint":false},{"pmid":"16518848","id":"PMC_16518848","title":"Acute monocytic leukemia with coexpression of minor BCR-ABL1 and PICALM-MLLT10 fusion genes along with overexpression of HOXA9.","date":"2006","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16518848","citation_count":5,"is_preprint":false},{"pmid":"27510896","id":"PMC_27510896","title":"Transient spontaneous remission in congenital MLL-AF10 rearranged acute myeloid leukemia presenting with cardiorespiratory failure and meconium ileus.","date":"2016","source":"Molecular and cellular pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/27510896","citation_count":5,"is_preprint":false},{"pmid":"15258852","id":"PMC_15258852","title":"Molecular genetics of the Alhambra (Drosophila AF10) complex locus of Drosophila.","date":"2004","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/15258852","citation_count":5,"is_preprint":false},{"pmid":"37995701","id":"PMC_37995701","title":"DOT1L interaction partner AF10 controls patterning of H3K79 methylation and RNA polymerase II to maintain cell identity.","date":"2023","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37995701","citation_count":5,"is_preprint":false},{"pmid":"28781666","id":"PMC_28781666","title":"Molecular studies reveal MLL-MLLT10/AF10 and ARID5B-MLL gene fusions displaced in a case of infantile acute lymphoblastic leukemia with complex karyotype.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28781666","citation_count":5,"is_preprint":false},{"pmid":"8946209","id":"PMC_8946209","title":"Gene BR140, which is related to AF10 and AF17, maps to chromosome band 3p25.","date":"1996","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/8946209","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47315,"output_tokens":8374,"usd":0.133777},"stage2":{"model":"claude-opus-4-6","input_tokens":12118,"output_tokens":5223,"usd":0.286747},"total_usd":0.420524,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"AF10 (MLLT10) contains a novel cysteine-rich motif termed the LAP/PHD finger (Leukemia-Associated Protein finger), which is proposed to bind zinc and function as a DNA-binding domain; this domain is disrupted in leukemia-associated chromosomal translocations.\",\n      \"method\": \"Sequence homology analysis and structural characterization of zinc finger motifs across multiple proteins\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/sequence-based prediction without direct biochemical validation of zinc binding or DNA binding in this paper\",\n      \"pmids\": [\"7568208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"AF10 contains conserved zinc finger and leucine zipper domains; in MLL-AF10 fusions resulting from t(10;11), the leucine zipper motif of AF10 is consistently juxtaposed onto the N-terminal region of MLL (HRX), suggesting a critical role for this leucine zipper dimerization motif in the chimeric oncoproteins.\",\n      \"method\": \"Reverse transcriptase-PCR and sequence analysis of leukemia patient samples\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — molecular characterization across 8 cases consistently showing leucine zipper retention, but no direct functional assay of the motif in this paper\",\n      \"pmids\": [\"7662954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"AF10 is fused to CALM (PICALM) in the t(10;11)(p13;q14) translocation in U937 cells, generating the CALM-AF10 fusion oncoprotein; CALM shares high homology with the murine ap-3 clathrin assembly protein and has a high-affinity binding site for phosphoinositols.\",\n      \"method\": \"Positional cloning and candidate gene approach; sequence analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational cloning study, highly cited, identified the fusion gene and characterized CALM's clathrin-assembly domain\",\n      \"pmids\": [\"8643484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The extended LAP/PHD-finger domain of AF10 mediates homo-oligomerization of the protein (demonstrated with recombinant AF10); AF10 also binds cruciform DNA via an AT-hook motif and localizes to the nucleus via a defined bipartite nuclear localization signal in its N-terminal region.\",\n      \"method\": \"Biochemical analysis with recombinant protein; DNA binding assays; subcellular fractionation\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro biochemical reconstitution with recombinant protein demonstrating oligomerization and DNA binding; multiple orthogonal methods\",\n      \"pmids\": [\"10860745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The leucine zipper domain of AF10 interacts with GAS41 (a glioblastoma amplified gene product homologous to yeast ANC1 and MLL fusion partners AF9/ENL); this interaction was confirmed by co-immunoprecipitation. Furthermore, GAS41 interacts with INI1 (SNF5 homolog, a SWI/SNF chromatin remodeling complex component), and INI1 was detected in AF10 immunoprecipitates, linking AF10 to SWI/SNF-mediated chromatin remodeling.\",\n      \"method\": \"Yeast two-hybrid screen followed by co-immunoprecipitation from cell line extracts\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid confirmed by reciprocal co-IP; multiple interaction partners identified\",\n      \"pmids\": [\"11756182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The synovial sarcoma-associated protein SYT physically interacts with AF10; the N-terminal region of SYT interacts with the C-terminal region of AF10 (outside known functional domains), confirmed by yeast two-hybrid, co-immunoprecipitation of endogenous and epitope-tagged proteins, and colocalization in transfected cells.\",\n      \"method\": \"Yeast two-hybrid screen; co-immunoprecipitation; colocalization by fluorescence microscopy\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple orthogonal confirmation methods (Y2H + co-IP + colocalization), single lab\",\n      \"pmids\": [\"11423977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The Drosophila AF10 homolog (dAF10/Alhambra) functions in heterochromatin-dependent gene silencing and interacts physically with Heterochromatin Protein 1 (HP1) both in vitro and in vivo, placing dAF10 in the heterochromatin-dependent silencing pathway.\",\n      \"method\": \"Genetic suppressor/enhancer analysis of position effect variegation; in vitro pull-down and in vivo co-immunoprecipitation with HP1\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic functional assay plus biochemical interaction confirmation, ortholog in Drosophila\",\n      \"pmids\": [\"11266362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The AF10 leucine zipper (a conserved 82-amino acid region comprising two adjacent alpha-helical domains) is necessary and sufficient for leukemic transformation by MLL-AF10; deletion of the 29-amino acid leucine zipper completely abrogated immortalizing and transforming activity. The same domain confers transcriptional activation properties on MLL-AF10.\",\n      \"method\": \"Retroviral transduction of primary murine myeloid progenitors; serial replating assays; in vivo leukemia induction; structure-function mutagenesis; transcriptional activation assays with GAL4 fusions\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — rigorous structure-function analysis with multiple deletion mutants, in vitro and in vivo assays, replicated across constructs\",\n      \"pmids\": [\"11986236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The leucine zipper domain of Drosophila AF10 (ALH) activates Polycomb group-responsive elements (PREs) when overexpressed in isolation, while the full-length protein does not (the PHD domain inhibits this activity); this derepression activity is conserved in the human AF10 leucine zipper expressed in Drosophila, and the MLL-AF10 fusion (which lacks the PHD domain) similarly activates PREs.\",\n      \"method\": \"Drosophila genetics; overexpression of isolated domains vs. full-length protein; PRE reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional domain dissection in Drosophila model with clear epistatic relationship between PHD and LZ domains\",\n      \"pmids\": [\"12482966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CALM-AF10 fusion causes leukemic transformation by upregulating Hoxa5 through recruitment of hDOT1L (H3K79 methyltransferase); hDOT1L interacts with AF10 and contributes to CALM-AF10-mediated leukemogenesis by (1) preventing nuclear export of CALM-AF10 and (2) upregulating Hoxa5 via H3K79 methylation.\",\n      \"method\": \"Retroviral transduction/bone marrow transformation assays; co-immunoprecipitation; ChIP; shRNA knockdown of hDOT1L; gene expression analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (co-IP, ChIP, functional transformation assay, knockdown rescue), highly cited foundational study\",\n      \"pmids\": [\"16921363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CATS (CALM interacting protein expressed in thymus and spleen), identified via yeast two-hybrid using the N-terminal half of CALM as bait, interacts with CALM at amino acids 221-335. CATS localizes to the nucleus/nucleolus and its expression markedly increases nuclear localization of both CALM and the leukemogenic CALM/AF10 fusion protein.\",\n      \"method\": \"Yeast two-hybrid screen; pull-down assays; co-immunoprecipitation; colocalization by fluorescence microscopy; subcellular localization analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple confirmation methods for interaction and localization effect, single lab\",\n      \"pmids\": [\"16491119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"AF10 interacts with the lymphoid transcription factor Ikaros via AF10's leucine zipper domain (confirmed by GST pull-down and co-immunoprecipitation); coexpression of CALM/AF10 (but not AF10 alone) alters the subcellular localization of Ikaros in murine fibroblasts, and AF10 reduces the transcriptional repressor activity of Ikaros.\",\n      \"method\": \"Yeast two-hybrid screen; GST pull-down; co-immunoprecipitation; subcellular localization by fluorescence microscopy; transcriptional repressor activity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods confirming interaction and functional consequence on Ikaros activity\",\n      \"pmids\": [\"18037964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"AF10-mediated transcription is enhanced by its interaction with FLRG (follistatin-related gene); the N-terminal PHD domain of AF10 mediates this interaction; FLRG promotes homo-oligomerization of AF10 and enhances AF10-mediated transactivation in reporter assays.\",\n      \"method\": \"Yeast two-hybrid screen; far-Western blot; co-immunoprecipitation; transactivation assays (Gal4-AF10 fusion in transfection)\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — interaction confirmed by multiple methods; functional consequence on transcription shown by reporter assay\",\n      \"pmids\": [\"17868029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The CALM-AF10 fusion protein globally reduces H3K79 methylation in leukemic cells by disrupting the normal AF10-mediated association of hDOT1L with chromatin, while simultaneously causing local H3K79 hypermethylation at Hoxa5 loci; cells with reduced H3K79 methylation show increased sensitivity to gamma-irradiation and chromosomal instability.\",\n      \"method\": \"ChIP; H3K79 methylation analysis in human and murine leukemic cells; gamma-irradiation sensitivity assays; cytogenetic analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic ChIP data in both human and murine cells, functional irradiation sensitivity assay, multiple orthogonal readouts\",\n      \"pmids\": [\"19443658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MLLT10/AF10 and DOT1L interact with TCF4/β-catenin in mouse intestinal crypts and are recruited to Wnt target gene loci in a β-catenin-dependent manner, resulting in H3K79 methylation over coding regions; MLLT10/AF10-DOT1L are essential and largely dedicated activators of Wnt-dependent transcription required for intestinal homeostasis.\",\n      \"method\": \"Proteomics (affinity purification/MS); co-immunoprecipitation; ChIP-seq; siRNA knockdown with expression arrays; zebrafish morpholino knockdown; apc-mutant zebrafish rescue experiments\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal approaches (proteomics, ChIP, knockdown, in vivo zebrafish genetics), strong mechanistic evidence\",\n      \"pmids\": [\"21103407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The clathrin-binding domain (C-terminal 248 aa of CALM) combined with the octapeptide motif-leucine zipper (OM-LZ) domain of AF10 is sufficient to induce AML in mice and recapitulates Hoxa cluster upregulation; structure-function analysis defines these two domains as the minimal oncogenic unit of CALM-AF10.\",\n      \"method\": \"Domain-deletion mutagenesis; retroviral transduction; colony-forming/serial replating assays; in vivo mouse leukemia model; gene expression analysis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — rigorous structure-function study with multiple deletion mutants tested in vitro and in vivo\",\n      \"pmids\": [\"21681188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In leukemia cells, full-length CALM-AF10 localizes to the nucleus with no consistent effect on growth factor endocytosis; CALM-AF10 suppresses H3K79 methylation regardless of clathrin binding; CALM-AF10 has a propensity to homo-oligomerize as demonstrated by FRET analysis, suggesting the clathrin-binding domain provides dimerization rather than endocytic disruption.\",\n      \"method\": \"Fluorescence resonance energy transfer (FRET); subcellular localization analysis; H3K79 methylation assay; endocytosis assays in leukemia cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — FRET for oligomerization, direct localization and methylation assays; single lab but multiple methods\",\n      \"pmids\": [\"21706055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MLL-AF10 and CALM-AF10-mediated leukemic transformation is dependent on the H3K79 methyltransferase DOT1L; conditional genetic knockout of Dot1l abolishes in vitro transformation and in vivo leukemia initiation/maintenance; pharmacological inhibition of DOT1L (EPZ004777) suppresses Hoxa cluster and Meis1 expression and selectively impairs proliferation of AF10-fusion leukemia cells.\",\n      \"method\": \"Conditional knockout mouse model (Dot1l flox); in vitro bone marrow transformation; in vivo leukemia transplantation; pharmacological inhibition with EPZ004777; gene expression analysis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic and pharmacological validation, in vitro and in vivo, replicated across two fusion types\",\n      \"pmids\": [\"23138183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The PHD1-PHD2 module of ZFP-1 (C. elegans AF10 ortholog) is essential for viability; the first PHD finger mediates preferential binding to H3K4-methylated histone H3 tails; ZFP-1 genome-wide localization peaks overlap with H3K4 methylation-enriched promoters of actively expressed genes, and H3K4 methylation is required for ZFP-1 promoter localization in embryos.\",\n      \"method\": \"Genetic deletion analysis in C. elegans; biochemical histone peptide binding assays; ChIP-seq/genomic localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic essentiality, biochemical binding assay for H3K4me, genome-wide localization in ortholog\",\n      \"pmids\": [\"23263989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The C. elegans AF10 ortholog ZFP-1 and its interacting partner DOT-1.1 globally reduce RNA Pol II transcription on essential widely expressed genes; the ZFP-1/DOT-1.1 complex promotes Pol II pausing and is associated with increased H3K79 methylation and decreased H2B monoubiquitination at highly expressed genes, constituting a negative feedback mechanism on transcription.\",\n      \"method\": \"Genomic approaches (ChIP-seq, RNA-seq); biochemical co-immunoprecipitation; genetic knockdown of ZFP-1 and DOT-1.1 in C. elegans\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide and biochemical approaches combined with genetic validation; mechanistically dissects AF10 ortholog function in transcription elongation\",\n      \"pmids\": [\"23806335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CALM contains a CRM1-dependent nuclear export signal (NES) that mediates cytoplasmic localization of CALM-AF10 and is necessary for CALM-AF10-dependent transformation; NES motifs from heterologous proteins fused to AF10 are sufficient to immortalize hematopoietic progenitors; the CALM NES is essential for Hoxa gene upregulation and aberrant H3K79 methylation, possibly by mislocalizing DOT1L.\",\n      \"method\": \"Mutagenesis of NES; retroviral transduction/bone marrow immortalization assays; Leptomycin B inhibition; gene expression analysis; H3K79 methylation analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — NES mutagenesis, heterologous NES substitution, pharmacological inhibition with mechanistic readouts\",\n      \"pmids\": [\"23487024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CRM1 (nuclear export receptor) localizes to HOXA gene loci where it recruits CALM-AF10 via the CALM NES, leading to transcriptional and epigenetic activation of HOXA genes; genetic and pharmacological inhibition of the CALM-CRM1 interaction prevents CALM-AF10 enrichment at HOXA chromatin and immediately abolishes HOXA transcription.\",\n      \"method\": \"ChIP; CRM1 inhibition (Leptomycin B); genetic disruption of NES; gene expression analysis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates CRM1 at HOXA loci, NES mutagenesis and pharmacological inhibition confirm mechanism with multiple readouts\",\n      \"pmids\": [\"25027513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The AF10 coiled-coil/leucine zipper domain interacts with GAS41 at a defined interaction site; a peptide inhibitor selected by phage display against the AF10 coiled-coil domain inhibits Hoxa gene expression when deployed in histiocytic lymphoma cells.\",\n      \"method\": \"Synthetic peptide mapping; phage display selection; CD spectroscopy; phage ELISA; mammalian cell transfection with inhibitory peptide; Hoxa gene expression analysis\",\n      \"journal\": \"Journal of peptide science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — interaction site mapping confirmed biochemically; functional inhibitory peptide validated in cells\",\n      \"pmids\": [\"24692230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nuclear export signal (NES) within CALM is necessary and sufficient for cytoplasmic localization of CALM-AF10; NES mutations eliminate the capacity of CALM-AF10 to immortalize bone marrow cells in vitro and to induce AML in mice; fusion of AF10 with the minimal NES is sufficient to immortalize cells and induce leukemia.\",\n      \"method\": \"NES mutagenesis; subcellular localization analysis; bone marrow immortalization assays; mouse leukemia model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis plus in vitro and in vivo functional validation; minimal NES sufficiency established\",\n      \"pmids\": [\"24397609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The PZP (PHD finger-Zn knuckle-PHD finger) domain of AF10 folds into a single module that recognizes amino acids 22-27 of histone H3 and specifically accommodates unmodified H3K27 (modification of H3K27 abrogates binding); crystal structure reveals H3 binding triggers rearrangement of the PZP module forming an H3(22-27)-accommodating channel with an unmodified H3K27 side chain encased in a compact hydrogen-bond acceptor-lined cage; in cells, PZP-H3 interaction is required for H3K79 dimethylation, DOT1L-target gene expression, and proliferation of DOT1L-addicted leukemic cells.\",\n      \"method\": \"Crystal structure determination; biochemical binding assays; mutagenesis of PZP domain; H3K79 methylation analysis in cells; gene expression analysis; cell proliferation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation by mutagenesis, biochemical binding assays, and cellular readouts; multiple orthogonal methods\",\n      \"pmids\": [\"26439302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mllt10 knockout mice exhibit midline facial cleft due to reduced proliferation of mesenchyme in developing nasal processes; H3K79 methylation is significantly decreased in nasal processes of Mllt10-KO embryos; AF10-dependent H3K79 methylation directly regulates AP2α expression in nasal processes, and suppression of H3K79 methylation fully mimics the Mllt10-KO phenotype.\",\n      \"method\": \"Mllt10 knockout mouse; phenotypic analysis; H3K79 methylation assay; gene expression analysis; ChIP for H3K79me at AP2α locus; pharmacological H3K79me suppression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with specific phenotypic readout, ChIP linking AF10 to H3K79me at a specific target gene, pharmacological recapitulation of phenotype\",\n      \"pmids\": [\"28931923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structures of apo AF10 OM-LZ domain and its complex with the coiled-coil domain of DOT1L reveal the molecular interface of AF10-DOT1L interaction; zinc stabilizes the DOT1L-AF10 complex; mutagenesis of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation.\",\n      \"method\": \"X-ray crystallography (apo and complex structures); mutagenesis of interface residues; leukemic transformation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus functional transformation assay; rigorous mechanistic study\",\n      \"pmids\": [\"29563185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AF10 (MLLT10) prevents somatic cell reprogramming by regulating DOT1L-mediated H3K79 methylation; proximity-based labeling identifies AF10 as a DOT1L interactor in somatic cells; AF10 suppression increases reprogramming efficiency; re-expression of wild-type AF10 but not a DOT1L binding-impaired mutant rescues H3K79 methylation and reduces reprogramming.\",\n      \"method\": \"Proximity-based labeling (BioID) proteomics; RNA interference; CRISPR/Cas9 knockout; reprogramming efficiency assays; H3K79 methylation analysis; transcriptomics\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — DOT1L-binding mutant rescue experiment directly links AF10's H3K79 regulation to reprogramming barrier; multiple orthogonal methods\",\n      \"pmids\": [\"34215314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The PZP domain of AF10, which binds nucleosomes through multivalent contacts with the histone H3 tail and DNA, is consistently impaired or deleted in leukemogenic AF10 translocations; incorporation of functional AF10 PZP into CALM-AF10 prevents transforming activity in vitro and in vivo, promotes nuclear localization of CALM-AF10, and is required for chromatin association; AF10 PZP discriminates against the repressive H3K27me3 mark.\",\n      \"method\": \"Crystallography; biochemical binding assays with nucleosome core particles; mutagenesis; bone marrow transformation assays in vitro and in vivo (mouse models); ChIP; subcellular fractionation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure, biochemical nucleosome binding, mutagenesis, and both in vitro and in vivo functional validation; multiple orthogonal methods\",\n      \"pmids\": [\"34226546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AF10 fusions (CALM-AF10 and MLL-AF10) activate a JAK/STAT-mediated inflammatory signaling cascade through direct recruitment of JAK1 kinase; genetic Jak1 deletion or pharmacological JAK/STAT inhibition elicits potent anti-oncogenic effects in mouse and human models of AF10 fusion AML.\",\n      \"method\": \"Inducible mouse AML models; transcriptomic, epigenomic, proteomic, and functional genomic approaches; co-immunoprecipitation for JAK1 recruitment; genetic Jak1 deletion; pharmacological JAK inhibition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive multi-omic characterization plus genetic and pharmacological validation of JAK1 as direct AF10 interactor and functional target\",\n      \"pmids\": [\"33690798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tip60 histone acetyltransferase is recruited by MLL-AF10 to the Hoxa9 locus where it acetylates H2A.Z to promote Hoxa9 gene expression; conditional deletion of Tip60 prevents development of MLL-AF10 leukemia.\",\n      \"method\": \"Co-immunoprecipitation (Tip60 recruitment by MLL-AF10); ChIP (Tip60 and H2A.Z acetylation at Hoxa9); conditional Tip60 knockout; leukemia development assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-based mechanism at specific locus, conditional KO with leukemia phenotype, co-IP confirming recruitment\",\n      \"pmids\": [\"33967269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DOT1L associates with MLLT10 (AF10) in testis; both proteins co-localize to sex chromatin in meiotic and post-meiotic germ cells in an inter-dependent manner; loss of either DOT1L or MLLT10 leads to reduced testis weight, decreased sperm count, male subfertility, and substantial retention of histones in epididymal sperm, demonstrating that H3K79 methylation promoted by the DOT1L-MLLT10 complex is essential for histone-to-protamine transition during spermiogenesis.\",\n      \"method\": \"Mouse knockout models (DOT1L and MLLT10); co-immunoprecipitation; immunofluorescence co-localization; H3K79me2 analysis; sperm histone retention assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dual KO with specific phenotype, co-IP and co-localization confirming complex, direct H3K79me2 measurement; multiple orthogonal methods\",\n      \"pmids\": [\"37082953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AF10 (MLLT10) controls patterning of H3K79me2/3 methylation at gene bodies; AF10 deletion evicts H3K79me2/3 and redistributes H3K79me1 to transcription start sites; AF10 loss also redistributes RNA Polymerase II to a pluripotent pattern at highly expressed housekeeping genes, facilitating iPSC formation without steady-state transcriptional changes. This identifies a specific function of H3K79me2/3 at gene bodies in reinforcing cell identity.\",\n      \"method\": \"Genetic AF10 deletion; chemical DOT1L inhibition; ChIP-seq for H3K79me1/2/3 and RNA Pol II; iPSC reprogramming efficiency assays\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic and chemical approaches combined with genome-wide ChIP-seq; mechanistically dissects how AF10 patterns H3K79me orders\",\n      \"pmids\": [\"37995701\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MLLT10/AF10 is a transcriptional co-regulator that functions as an essential cofactor for the H3K79 methyltransferase DOT1L, recruiting it to gene bodies (including HOXA cluster genes and Wnt targets) through direct protein-protein interaction mediated by the AF10 octapeptide motif-leucine zipper (OM-LZ) domain, while its N-terminal PZP domain reads unmodified H3K27 on nucleosomes to direct chromatin targeting; in leukemic translocations, the PZP domain is lost and the OM-LZ is fused to MLL or CALM, misrecruiting DOT1L to HOXA loci (driven partly by CALM's CRM1-dependent nuclear export signal and cytoplasmic-nuclear shuttling), causing H3K79 hypermethylation and HOXA gene upregulation that drives transformation, while additionally recruiting JAK1 kinase to activate JAK/STAT inflammatory signaling; in normal physiology, AF10-DOT1L deposits H3K79me2/3 at gene bodies to maintain somatic cell identity, regulate Wnt target gene transcription in intestinal crypts, regulate AP2α expression in craniofacial development, and promote histone-to-protamine transition during spermiogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MLLT10 (AF10) is a chromatin reader and transcriptional co-regulator that directs the H3K79 methyltransferase DOT1L to gene bodies, thereby patterning H3K79me2/3 to maintain somatic cell identity, regulate Wnt target gene transcription in intestinal crypts, control craniofacial morphogenesis, and promote histone-to-protamine transition during spermiogenesis [PMID:21103407, PMID:28931923, PMID:37082953, PMID:37995701]. Its N-terminal PZP domain binds nucleosomes by recognizing unmodified H3K27 and engaging DNA, while its C-terminal OM-LZ domain directly contacts the DOT1L coiled-coil, with crystal structures defining both interfaces; the PZP domain acts as an autoinhibitory module that restrains the transcriptional activation capacity of the OM-LZ [PMID:26439302, PMID:34226546, PMID:29563185, PMID:12482966]. In recurrent leukemia-associated translocations (MLL-AF10 and CALM-AF10), the PZP domain is lost and the OM-LZ is retained, causing DOT1L misrecruitment, H3K79 hypermethylation at HOXA loci, HOXA/MEIS1 upregulation, and JAK1-mediated JAK/STAT inflammatory signaling that together drive myeloid transformation [PMID:16921363, PMID:23138183, PMID:33690798, PMID:25027513]. AF10 also bridges DOT1L to additional chromatin regulators including GAS41 (linking to SWI/SNF remodeling), Ikaros, and the TCF4/β-catenin complex, and its deletion redistributes RNA Polymerase II to a pluripotent pattern, establishing AF10-dependent H3K79me2/3 as a barrier to somatic cell reprogramming [PMID:11756182, PMID:18037964, PMID:21103407, PMID:34215314, PMID:37995701].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of AF10's domain architecture — a zinc-finger/PHD module and leucine zipper — in leukemia translocations established that the leucine zipper is consistently retained in MLL-AF10 fusions, pointing to it as functionally critical for oncogenesis.\",\n      \"evidence\": \"Sequence analysis and RT-PCR characterization of multiple t(10;11) leukemia patient samples\",\n      \"pmids\": [\"7568208\", \"7662954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct functional test of leucine zipper in transformation\", \"DNA-binding activity of PHD finger predicted but not biochemically validated\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Discovery of the CALM-AF10 fusion in t(10;11)(p13;q14) revealed a second translocation partner for AF10 and introduced the clathrin-assembly protein CALM into leukemia biology.\",\n      \"evidence\": \"Positional cloning from U937 cells identifying the CALM-AF10 fusion gene\",\n      \"pmids\": [\"8643484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CALM contributes to transformation unknown\", \"Whether clathrin-binding function is relevant to leukemogenesis unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Biochemical reconstitution showed the PHD/LAP domain mediates AF10 homo-oligomerization and that AF10 binds DNA via an AT-hook motif, establishing AF10 as a chromatin-associated protein.\",\n      \"evidence\": \"Recombinant protein oligomerization assays, DNA binding assays, and subcellular fractionation\",\n      \"pmids\": [\"10860745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological chromatin targets unknown\", \"Relevance of AT-hook DNA binding to gene regulation untested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of GAS41 and INI1/SNF5 as AF10 leucine-zipper interactors linked AF10 to SWI/SNF chromatin remodeling, while Drosophila AF10 (Alhambra) was shown to interact with HP1 and function in heterochromatin-dependent silencing, establishing AF10 as a chromatin regulatory factor across species.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells; genetic suppressor analysis of position-effect variegation and HP1 pull-down in Drosophila\",\n      \"pmids\": [\"11756182\", \"11266362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GAS41-AF10 interaction is relevant in leukemia unclear\", \"Mechanism of HP1 interaction in mammalian AF10 not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Structure-function analysis proved the AF10 leucine zipper is necessary and sufficient for MLL-AF10-mediated leukemic transformation, directly linking a specific AF10 domain to oncogenic activity.\",\n      \"evidence\": \"Retroviral transduction of murine myeloid progenitors with deletion mutants; serial replating and in vivo leukemia induction\",\n      \"pmids\": [\"11986236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The leucine zipper's binding partner mediating transformation not yet identified\", \"Downstream transcriptional targets not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Drosophila experiments revealed that the AF10 PHD domain autoinhibits the transcriptional activation capacity of the leucine zipper, explaining why MLL-AF10 (which lacks the PHD) derepresses Polycomb targets — establishing an intramolecular regulatory mechanism.\",\n      \"evidence\": \"Overexpression of isolated AF10 domains versus full-length protein in Drosophila PRE reporter assays\",\n      \"pmids\": [\"12482966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Autoinhibition not demonstrated with purified mammalian AF10\", \"Polycomb group derepression mechanism in mammalian leukemia not confirmed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The pivotal discovery that DOT1L (H3K79 methyltransferase) is recruited by AF10 and is required for CALM-AF10-mediated Hoxa5 upregulation and leukemogenesis established the AF10-DOT1L axis as the central oncogenic mechanism in AF10-rearranged leukemia.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP for H3K79me at Hoxa5, shRNA knockdown of DOT1L, bone marrow transformation assays\",\n      \"pmids\": [\"16921363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface between AF10 and DOT1L not structurally characterized\", \"Whether DOT1L recruitment is the sole mechanism of transformation unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"CALM-AF10 was found to globally reduce H3K79 methylation while locally hypermethylating Hoxa5, revealing that the fusion disrupts normal AF10-DOT1L chromatin distribution and causes genomic instability through global H3K79me depletion.\",\n      \"evidence\": \"ChIP and H3K79me analysis in human and murine leukemic cells; gamma-irradiation sensitivity and cytogenetic assays\",\n      \"pmids\": [\"19443658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of selective local hypermethylation versus global hypomethylation not resolved\", \"Whether genomic instability contributes to disease progression independently unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"AF10 and DOT1L were shown to be recruited to Wnt target genes by TCF4/β-catenin in intestinal crypts, depositing H3K79me over coding regions, thereby establishing the first physiological role of AF10 in normal tissue homeostasis beyond leukemia.\",\n      \"evidence\": \"Affinity purification/MS proteomics, co-IP, ChIP-seq, siRNA knockdown with expression arrays, zebrafish morpholino and apc-mutant rescue\",\n      \"pmids\": [\"21103407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AF10-DOT1L has Wnt-independent roles in the intestine not addressed\", \"Tissue-specific regulation of AF10-TCF4 interaction unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Minimal-domain analyses of CALM-AF10 defined the CALM clathrin-binding domain plus AF10 OM-LZ as the minimal oncogenic unit, while FRET showed CALM-AF10 homo-oligomerizes, suggesting the clathrin domain contributes via dimerization rather than endocytic disruption.\",\n      \"evidence\": \"Domain-deletion mutagenesis with in vitro and in vivo transformation assays; FRET analysis of oligomerization\",\n      \"pmids\": [\"21681188\", \"21706055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CALM-mediated oligomerization not resolved\", \"Whether oligomerization is required for DOT1L recruitment unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"C. elegans ortholog studies revealed that AF10 (ZFP-1) PHD1 binds H3K4-methylated tails and localizes to active promoters genome-wide, identifying a conserved chromatin-reading function distinct from the H3K27-recognition later found for the PZP domain.\",\n      \"evidence\": \"Genetic deletion, histone peptide binding assays, and ChIP-seq in C. elegans\",\n      \"pmids\": [\"23263989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian AF10 PZP also reads H3K4me not tested\", \"Potential divergence between nematode and mammalian AF10 chromatin reading\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genetic knockout and pharmacological inhibition of DOT1L definitively established that H3K79 methyltransferase activity is required for both MLL-AF10 and CALM-AF10 leukemic transformation, validating DOT1L as a therapeutic target.\",\n      \"evidence\": \"Conditional Dot1l knockout mouse; EPZ004777 inhibitor; in vitro transformation and in vivo leukemia assays; Hoxa/Meis1 expression analysis\",\n      \"pmids\": [\"23138183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DOT1L inhibition has sufficient therapeutic window in patients unknown\", \"Non-H3K79me mechanisms of AF10 fusion oncogenesis not excluded\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The CALM NES (CRM1-dependent nuclear export signal) was shown to be necessary and sufficient for CALM-AF10 leukemogenesis, with CRM1 recruiting the fusion to HOXA chromatin — resolving a long-standing question of why a clathrin-adaptor protein drives nuclear oncogenesis.\",\n      \"evidence\": \"NES mutagenesis, heterologous NES substitution, Leptomycin B inhibition, ChIP showing CRM1 at HOXA loci, bone marrow transformation and mouse leukemia models\",\n      \"pmids\": [\"23487024\", \"25027513\", \"24397609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CRM1 specifically targets HOXA loci mechanistically unclear\", \"Whether other NES-containing fusions can similarly transform unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genome-wide studies in C. elegans showed that the ZFP-1/DOT-1.1 complex promotes RNA Pol II pausing at highly expressed genes, constituting a negative transcriptional feedback mechanism — providing the first evidence that AF10-DOT1L restrains rather than simply activates transcription.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, and genetic knockdown in C. elegans\",\n      \"pmids\": [\"23806335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Pol II pausing function is conserved in mammalian AF10-DOT1L not tested\", \"Mechanism linking H3K79me to pausing not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structure of the AF10 PZP domain bound to H3 revealed it recognizes unmodified H3K27 through a hydrogen-bond cage, directly explaining why H3K27 methylation antagonizes AF10 chromatin targeting and why PZP loss in translocations deregulates DOT1L.\",\n      \"evidence\": \"X-ray crystallography, biochemical binding assays with modified histone peptides, mutagenesis, cellular H3K79me and proliferation assays\",\n      \"pmids\": [\"26439302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PZP-H3K27 reading is coordinated with DOT1L catalysis not structurally resolved\", \"Whether PZP also reads nucleosomal DNA contacts not addressed in this study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mllt10 knockout mice exhibited midline facial cleft with reduced H3K79me at the AP2α locus, establishing AF10 as essential for craniofacial development through DOT1L-dependent regulation of specific developmental genes.\",\n      \"evidence\": \"Mllt10 knockout mouse; H3K79me ChIP at AP2α; pharmacological H3K79me suppression recapitulating phenotype\",\n      \"pmids\": [\"28931923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other developmental targets beyond AP2α are regulated by AF10 in facial development unknown\", \"Human craniofacial disease association not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Crystal structures of the AF10 OM-LZ domain alone and in complex with DOT1L's coiled-coil defined the molecular interface and showed zinc stabilizes the complex; interface mutations abolished leukemic transformation, providing a structural blueprint for therapeutic disruption.\",\n      \"evidence\": \"X-ray crystallography of apo and complex; interface mutagenesis; leukemic transformation assays\",\n      \"pmids\": [\"29563185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No small-molecule inhibitor of the AF10-DOT1L interface developed\", \"Whether interface disruption affects normal AF10 physiology not assessed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies converged to show that AF10 PZP binds nucleosomes through multivalent H3-tail and DNA contacts, that PZP incorporation into CALM-AF10 suppresses transformation, that AF10 fusions recruit JAK1 to activate JAK/STAT signaling as a parallel oncogenic mechanism, and that Tip60 is recruited by MLL-AF10 to acetylate H2A.Z at Hoxa9 — revealing transformation requires multiple epigenetic and signaling axes.\",\n      \"evidence\": \"Crystallography and nucleosome binding; in vivo mouse transformation with PZP-containing constructs; multi-omic profiling with genetic Jak1 deletion and JAK inhibition; co-IP and conditional Tip60 knockout\",\n      \"pmids\": [\"34226546\", \"33690798\", \"33967269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of JAK/STAT versus DOT1L axis to transformation not quantified\", \"Whether Tip60 recruitment is specific to MLL-AF10 or shared with CALM-AF10 unclear\", \"Structural basis of JAK1 recruitment by AF10 not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"AF10 was identified as a DOT1L cofactor that maintains the somatic cell epigenetic barrier to reprogramming: AF10 loss facilitates iPSC formation, and rescue requires intact DOT1L-binding capacity, linking AF10-H3K79me to cell identity maintenance.\",\n      \"evidence\": \"BioID proximity labeling, RNAi, CRISPR knockout, DOT1L-binding-impaired mutant rescue, reprogramming efficiency assays\",\n      \"pmids\": [\"34215314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific loci lose H3K79me to permit reprogramming not mapped genome-wide\", \"Whether AF10 has DOT1L-independent roles in cell identity not excluded\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"AF10 deletion evicts H3K79me2/3 from gene bodies and redistributes H3K79me1 to TSSs and Pol II to a pluripotent pattern without altering steady-state transcription, defining a specific gene-body H3K79me2/3 function in reinforcing cell identity; separately, DOT1L-MLLT10 was shown essential for spermiogenesis through histone-to-protamine transition.\",\n      \"evidence\": \"Genetic AF10 deletion plus ChIP-seq for H3K79me1/2/3 and Pol II; DOT1L and MLLT10 knockout mice with sperm histone retention assays and co-IP/co-localization in testis\",\n      \"pmids\": [\"37995701\", \"37082953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H3K79me2/3 at gene bodies mechanistically prevents Pol II redistribution unknown\", \"Whether the spermiogenesis phenotype involves the same PZP-dependent chromatin reading as somatic cells not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of how PZP nucleosome reading is coordinated with OM-LZ-mediated DOT1L recruitment within the full-length AF10-DOT1L complex on chromatin; how H3K79me2/3 at gene bodies mechanistically reinforces somatic Pol II distribution; the relative therapeutic tractability of disrupting the AF10-DOT1L interface versus JAK/STAT inhibition in AF10-rearranged leukemia; and whether AF10 has DOT1L-independent functions in mammalian cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length AF10-DOT1L-nucleosome structural model exists\", \"Mechanism by which gene-body H3K79me2/3 controls Pol II distribution remains undefined\", \"Therapeutic targeting of AF10-DOT1L interface not achieved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [24, 28, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 14, 17, 27, 32]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 8, 12, 14, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 10, 28]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [24, 28, 31, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 13, 17, 24, 26, 27, 32]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 14, 19, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 29]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [25, 31]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 9, 15, 17, 20, 21, 23, 29]}\n    ],\n    \"complexes\": [\n      \"DOT1L complex\",\n      \"TCF4/β-catenin transcriptional complex\"\n    ],\n    \"partners\": [\n      \"DOT1L\",\n      \"GAS41\",\n      \"PICALM\",\n      \"KMT2A\",\n      \"JAK1\",\n      \"KAT5\",\n      \"IKZF1\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}