Affinage

MLLT10

Protein AF-10 · UniProt P55197

Length
1068 aa
Mass
113.3 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1995 Medium

    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

    PMID:7568208 PMID:7662954

    Open questions at the time
    • No direct functional test of leucine zipper in transformation
    • DNA-binding activity of PHD finger predicted but not biochemically validated
  2. 1996 High

    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

    PMID:8643484

    Open questions at the time
    • Mechanism by which CALM contributes to transformation unknown
    • Whether clathrin-binding function is relevant to leukemogenesis unclear
  3. 2000 High

    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

    PMID:10860745

    Open questions at the time
    • Physiological chromatin targets unknown
    • Relevance of AT-hook DNA binding to gene regulation untested
  4. 2001 High

    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

    PMID:11266362 PMID:11756182

    Open questions at the time
    • Whether GAS41-AF10 interaction is relevant in leukemia unclear
    • Mechanism of HP1 interaction in mammalian AF10 not tested
  5. 2002 High

    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

    PMID:11986236

    Open questions at the time
    • The leucine zipper's binding partner mediating transformation not yet identified
    • Downstream transcriptional targets not defined
  6. 2003 Medium

    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

    PMID:12482966

    Open questions at the time
    • Autoinhibition not demonstrated with purified mammalian AF10
    • Polycomb group derepression mechanism in mammalian leukemia not confirmed
  7. 2006 High

    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

    PMID:16921363

    Open questions at the time
    • Direct binding interface between AF10 and DOT1L not structurally characterized
    • Whether DOT1L recruitment is the sole mechanism of transformation unknown
  8. 2009 High

    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

    PMID:19443658

    Open questions at the time
    • Mechanism of selective local hypermethylation versus global hypomethylation not resolved
    • Whether genomic instability contributes to disease progression independently unclear
  9. 2010 High

    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

    PMID:21103407

    Open questions at the time
    • Whether AF10-DOT1L has Wnt-independent roles in the intestine not addressed
    • Tissue-specific regulation of AF10-TCF4 interaction unclear
  10. 2011 High

    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

    PMID:21681188 PMID:21706055

    Open questions at the time
    • Structural basis of CALM-mediated oligomerization not resolved
    • Whether oligomerization is required for DOT1L recruitment unknown
  11. 2012 High

    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

    PMID:23263989

    Open questions at the time
    • Whether mammalian AF10 PZP also reads H3K4me not tested
    • Potential divergence between nematode and mammalian AF10 chromatin reading
  12. 2012 High

    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

    PMID:23138183

    Open questions at the time
    • Whether DOT1L inhibition has sufficient therapeutic window in patients unknown
    • Non-H3K79me mechanisms of AF10 fusion oncogenesis not excluded
  13. 2013 High

    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

    PMID:23487024 PMID:24397609 PMID:25027513

    Open questions at the time
    • How CRM1 specifically targets HOXA loci mechanistically unclear
    • Whether other NES-containing fusions can similarly transform unclear
  14. 2013 High

    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

    PMID:23806335

    Open questions at the time
    • Whether Pol II pausing function is conserved in mammalian AF10-DOT1L not tested
    • Mechanism linking H3K79me to pausing not defined
  15. 2015 High

    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

    PMID:26439302

    Open questions at the time
    • How PZP-H3K27 reading is coordinated with DOT1L catalysis not structurally resolved
    • Whether PZP also reads nucleosomal DNA contacts not addressed in this study
  16. 2017 High

    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

    PMID:28931923

    Open questions at the time
    • Whether other developmental targets beyond AP2α are regulated by AF10 in facial development unknown
    • Human craniofacial disease association not established
  17. 2018 High

    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

    PMID:29563185

    Open questions at the time
    • No small-molecule inhibitor of the AF10-DOT1L interface developed
    • Whether interface disruption affects normal AF10 physiology not assessed
  18. 2021 High

    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

    PMID:33690798 PMID:33967269 PMID:34226546

    Open questions at the time
    • 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
  19. 2021 High

    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

    PMID:34215314

    Open questions at the time
    • Which specific loci lose H3K79me to permit reprogramming not mapped genome-wide
    • Whether AF10 has DOT1L-independent roles in cell identity not excluded
  20. 2023 High

    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

    PMID:37082953 PMID:37995701

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140110 transcription regulator activity 5 GO:0042393 histone binding 3
Localization
GO:0005694 chromosome 4 GO:0005634 nucleus 3
Pathway
R-HSA-1643685 Disease 8 R-HSA-4839726 Chromatin organization 7 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2
Partners
CTNNB1DOT1LGAS41IKZF1JAK1KAT5KMT2APICALM
Complex memberships
DOT1L complexTCF4/β-catenin transcriptional complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 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. Sequence homology analysis and structural characterization of zinc finger motifs across multiple proteins Proceedings of the National Academy of Sciences of the United States of America Low 7568208
1995 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. Reverse transcriptase-PCR and sequence analysis of leukemia patient samples Blood Medium 7662954
1996 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. Positional cloning and candidate gene approach; sequence analysis Proceedings of the National Academy of Sciences of the United States of America High 8643484
2000 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. Biochemical analysis with recombinant protein; DNA binding assays; subcellular fractionation Journal of molecular biology High 10860745
2001 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. Yeast two-hybrid screen followed by co-immunoprecipitation from cell line extracts Blood High 11756182
2001 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. Yeast two-hybrid screen; co-immunoprecipitation; colocalization by fluorescence microscopy Oncogene Medium 11423977
2001 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. Genetic suppressor/enhancer analysis of position effect variegation; in vitro pull-down and in vivo co-immunoprecipitation with HP1 EMBO reports Medium 11266362
2002 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. Retroviral transduction of primary murine myeloid progenitors; serial replating assays; in vivo leukemia induction; structure-function mutagenesis; transcriptional activation assays with GAL4 fusions Blood High 11986236
2003 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. Drosophila genetics; overexpression of isolated domains vs. full-length protein; PRE reporter assays Molecular and cellular biology Medium 12482966
2006 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. Retroviral transduction/bone marrow transformation assays; co-immunoprecipitation; ChIP; shRNA knockdown of hDOT1L; gene expression analysis Nature cell biology High 16921363
2006 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. Yeast two-hybrid screen; pull-down assays; co-immunoprecipitation; colocalization by fluorescence microscopy; subcellular localization analysis Oncogene Medium 16491119
2007 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. Yeast two-hybrid screen; GST pull-down; co-immunoprecipitation; subcellular localization by fluorescence microscopy; transcriptional repressor activity assays Oncogene Medium 18037964
2007 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. Yeast two-hybrid screen; far-Western blot; co-immunoprecipitation; transactivation assays (Gal4-AF10 fusion in transfection) Biology of the cell Medium 17868029
2009 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. ChIP; H3K79 methylation analysis in human and murine leukemic cells; gamma-irradiation sensitivity assays; cytogenetic analysis Blood High 19443658
2010 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. Proteomics (affinity purification/MS); co-immunoprecipitation; ChIP-seq; siRNA knockdown with expression arrays; zebrafish morpholino knockdown; apc-mutant zebrafish rescue experiments PLoS biology High 21103407
2011 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. Domain-deletion mutagenesis; retroviral transduction; colony-forming/serial replating assays; in vivo mouse leukemia model; gene expression analysis Leukemia High 21681188
2011 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. Fluorescence resonance energy transfer (FRET); subcellular localization analysis; H3K79 methylation assay; endocytosis assays in leukemia cells Oncogene Medium 21706055
2012 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. Conditional knockout mouse model (Dot1l flox); in vitro bone marrow transformation; in vivo leukemia transplantation; pharmacological inhibition with EPZ004777; gene expression analysis Leukemia High 23138183
2012 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. Genetic deletion analysis in C. elegans; biochemical histone peptide binding assays; ChIP-seq/genomic localization Molecular and cellular biology High 23263989
2013 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. Genomic approaches (ChIP-seq, RNA-seq); biochemical co-immunoprecipitation; genetic knockdown of ZFP-1 and DOT-1.1 in C. elegans Molecular cell High 23806335
2013 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. Mutagenesis of NES; retroviral transduction/bone marrow immortalization assays; Leptomycin B inhibition; gene expression analysis; H3K79 methylation analysis Blood High 23487024
2014 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. ChIP; CRM1 inhibition (Leptomycin B); genetic disruption of NES; gene expression analysis Leukemia High 25027513
2014 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. Synthetic peptide mapping; phage display selection; CD spectroscopy; phage ELISA; mammalian cell transfection with inhibitory peptide; Hoxa gene expression analysis Journal of peptide science Medium 24692230
2014 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. NES mutagenesis; subcellular localization analysis; bone marrow immortalization assays; mouse leukemia model Cancer science High 24397609
2015 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. Crystal structure determination; biochemical binding assays; mutagenesis of PZP domain; H3K79 methylation analysis in cells; gene expression analysis; cell proliferation assays Molecular cell High 26439302
2017 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. Mllt10 knockout mouse; phenotypic analysis; H3K79 methylation assay; gene expression analysis; ChIP for H3K79me at AP2α locus; pharmacological H3K79me suppression Scientific reports High 28931923
2018 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. X-ray crystallography (apo and complex structures); mutagenesis of interface residues; leukemic transformation assays Genes & development High 29563185
2021 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. Proximity-based labeling (BioID) proteomics; RNA interference; CRISPR/Cas9 knockout; reprogramming efficiency assays; H3K79 methylation analysis; transcriptomics Epigenetics & chromatin High 34215314
2021 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. Crystallography; biochemical binding assays with nucleosome core particles; mutagenesis; bone marrow transformation assays in vitro and in vivo (mouse models); ChIP; subcellular fractionation Nature communications High 34226546
2021 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. Inducible mouse AML models; transcriptomic, epigenomic, proteomic, and functional genomic approaches; co-immunoprecipitation for JAK1 recruitment; genetic Jak1 deletion; pharmacological JAK inhibition Blood High 33690798
2021 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. Co-immunoprecipitation (Tip60 recruitment by MLL-AF10); ChIP (Tip60 and H2A.Z acetylation at Hoxa9); conditional Tip60 knockout; leukemia development assay Leukemia High 33967269
2023 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. Mouse knockout models (DOT1L and MLLT10); co-immunoprecipitation; immunofluorescence co-localization; H3K79me2 analysis; sperm histone retention assay Development (Cambridge, England) High 37082953
2023 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. Genetic AF10 deletion; chemical DOT1L inhibition; ChIP-seq for H3K79me1/2/3 and RNA Pol II; iPSC reprogramming efficiency assays Stem cell reports High 37995701

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 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. Proceedings of the National Academy of Sciences of the United States of America 267 8643484
2006 Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L. Nature cell biology 147 16921363
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