Affinage

Showing MLLT10 — AF10 is a alias.

MLLT10

Protein AF-10 · UniProt P55197

Length
1068 aa
Mass
113.3 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MLLT10/AF10 is a nuclear chromatin-associated cofactor that targets the H3K79 methyltransferase DOT1L to active chromatin, governing transcriptional programs in development, stem cell identity, and leukemia (PMID:23138183, PMID:26439302, PMID:37995701). AF10 binds DOT1L directly through its octapeptide motif-leucine zipper (OM-LZ) domain, an interaction resolved by crystallography and stabilized by zinc, and disruption of this interface abolishes MLL-AF10 leukemic transformation (PMID:29563185). Its N-terminal PZP module (PHD-Zn knuckle-PHD) engages the nucleosome through multivalent contacts with unmodified H3 (specifically unmethylated H3K27) and DNA, discriminating against repressive H3K27me3, thereby directing DOT1L-dependent H3K79 di- and trimethylation to gene bodies of active genes; PZP recognition is required for H3K79me2 deposition, DOT1L-target gene expression, and proliferation of DOT1L-addicted cells (PMID:26439302, PMID:34226546). AF10 controls the higher-order patterning of H3K79 methylation across the genome and the redistribution of RNA Pol II, acting as a barrier to somatic cell reprogramming that maintains cell identity (PMID:34215314, PMID:37995701). Through this DOT1L axis, AF10 directly regulates AP2α expression and midline facial development (PMID:28931923) and drives histone-to-protamine replacement during spermiogenesis, where DOT1L and MLLT10 co-localize to sex chromatin and are mutually required for germ-cell H3K79me2 (PMID:37082953). In Wnt signaling, the AF10-DOT1L complex is recruited by TCF4/β-catenin to deposit H3K79 methylation over Wnt target gene coding regions, supporting intestinal proliferation (PMID:21103407). In leukemia, AF10 fusion oncoproteins (MLL-AF10, CALM/PICALM-AF10) misdirect DOT1L to drive aberrant H3K79 methylation and HOXA cluster upregulation; the minimal transforming unit is the AF10 OM-LZ together with the CALM clathrin-binding/NES region, with the CALM NES recruiting CRM1 to HOXA chromatin (PMID:21681188, PMID:23138183, PMID:23487024, PMID:25027513). AF10 fusions additionally recruit Tip60 to acetylate H2A.Z at Hoxa9 and directly recruit JAK1 to activate JAK/STAT inflammatory signaling, both of which are required for leukemogenesis (PMID:33690798, PMID:33967269).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 Medium

    Established AF10's domain architecture and its central role in leukemia, defining the LAP/PHD zinc finger and identifying the leucine zipper as the element consistently fused to MLL in t(10;11) AML.

    Evidence Sequence homology analysis of zinc finger motifs and breakpoint mapping in AML patient samples

    PMID:7568208 PMID:7662954

    Open questions at the time
    • LAP/PHD DNA-binding was predicted, not demonstrated
    • no mechanistic link to a methyltransferase yet
    • functional consequence of the leucine zipper fusion unresolved
  2. 2000 Medium

    Defined the biochemical properties of AF10 domains, showing the extended LAP/PHD finger drives homo-oligomerization, an AT-hook binds cruciform DNA, and a bipartite NLS directs nuclear localization.

    Evidence Biochemical reconstitution with recombinant AF10, GST pulldown, DNA-binding assay, and subcellular fractionation

    PMID:10860745

    Open questions at the time
    • physiological relevance of cruciform DNA binding unclear
    • oligomerization partners in cells not defined
    • no chromatin target identified
  3. 2001 Medium

    Linked AF10 to chromatin silencing and other binding partners, connecting it to HP1-dependent heterochromatin in Drosophila and identifying SYT and (later) FLRG as interactors.

    Evidence In vitro/in vivo binding, co-IP, position-effect-variegation genetics in Drosophila, and yeast two-hybrid with domain mapping

    PMID:11266362 PMID:11423977 PMID:17868029

    Open questions at the time
    • mechanistic role of HP1, SYT, FLRG interactions in mammalian AF10 function unestablished
    • ortholog-based silencing data may not transfer directly
    • FLRG/SYT not connected to the DOT1L axis
  4. 2002 High

    Showed the AF10 leucine zipper is necessary and sufficient for MLL-AF10 transformation and confers transcriptional activation, and placed AF10 in proximity to SWI/SNF via GAS41 and INI1.

    Evidence Deletion-mutant retroviral transformation in murine progenitors, serial replating, GAL4 reporter assays, and yeast two-hybrid/co-IP

    PMID:11756182 PMID:11986236

    Open questions at the time
    • the leucine-zipper effector partner was not yet identified
    • relationship between SWI/SNF association and transformation unclear
  5. 2006 High

    Identified DOT1L as the key AF10 effector in leukemia, showing CALM-AF10 binds hDOT1L through the AF10 moiety to drive H3K79 methylation and Hoxa upregulation.

    Evidence Co-IP, ChIP for H3K79me at Hoxa5, nuclear export assay, and retroviral transformation; plus Ikaros and CATS interaction mapping

    PMID:16491119 PMID:16921363 PMID:18037964

    Open questions at the time
    • how AF10 normally targets DOT1L to chromatin not yet defined
    • global versus local H3K79me effects unresolved
  6. 2009 Medium

    Revealed that CALM-AF10 disrupts normal AF10-mediated DOT1L-chromatin association, causing global H3K79me loss, genomic instability, and irradiation sensitivity.

    Evidence ChIP for H3K79me, co-IP, gamma-irradiation sensitivity assays, and cytogenetics of patient samples

    PMID:19443658

    Open questions at the time
    • reconciling global H3K79me loss with locus-specific HOXA gain unresolved
    • molecular basis of mistargeting not yet structural
  7. 2010 High

    Defined a physiological developmental role by showing the AF10-DOT1L complex is recruited by TCF4/β-catenin to deposit H3K79me over Wnt target gene coding regions and drive intestinal proliferation.

    Evidence TCF4/β-catenin proteomics, ChIP-H3K79me, siRNA expression arrays, and zebrafish epistasis with apc mutants

    PMID:21103407

    Open questions at the time
    • direct contacts between AF10 and the TCF4/β-catenin module not mapped
    • selectivity for Wnt over other active genes unexplained
  8. 2011 High

    Defined the minimal CALM-AF10 transforming unit (CALM clathrin-binding domain plus AF10 OM-LZ) and showed full-length CALM-AF10 localizes to the nucleus, homo-oligomerizes, and suppresses H3K79me independent of clathrin.

    Evidence Domain-deletion colony and mouse leukemia assays, FRET oligomerization analysis, and ChIP for H3K79me

    PMID:21681188 PMID:21706055

    Open questions at the time
    • mechanism connecting oligomerization to H3K79me dysregulation unclear
    • role of CALM moiety in DOT1L mistargeting not yet defined
  9. 2012 High

    Established DOT1L as the genetic and pharmacological dependency of AF10-fusion leukemia and characterized AF10/DOT1L as a repressive elongation modulator in the ortholog.

    Evidence Conditional Dot1l knockout, EPZ004777 inhibition, and in vitro/in vivo leukemia models; plus C. elegans ZFP-1/DOT-1.1 ChIP-seq/RNA-seq

    PMID:23138183 PMID:23263989 PMID:23806335

    Open questions at the time
    • ortholog ZFP-1 repressive role contrasts with activating mammalian role, leaving directionality context-dependent
    • PHD-module H3K4me reading shown in ortholog, not yet human
  10. 2014 High

    Resolved how CALM-AF10 reaches HOXA chromatin, showing the CALM CRM1-dependent NES is required for transformation and recruits CRM1, which itself occupies HOXA loci and brings in CALM-AF10.

    Evidence NES mutagenesis, heterologous NES fusions, Leptomycin B treatment, and ChIP for CRM1 and CALM-AF10 at HOXA

    PMID:23487024 PMID:25027513

    Open questions at the time
    • how CRM1 selects HOXA chromatin not defined
    • generalizability beyond CALM-AF10 to MLL-AF10 unclear
  11. 2015 High

    Provided the structural basis for AF10 chromatin targeting, showing the PZP module reads unmodified H3K27 to license DOT1L-dependent H3K79me2 and DOT1L-target gene expression.

    Evidence Crystal structure of PZP-H3 complex, interface mutagenesis, histone peptide pulldowns, and ChIP/proliferation assays in cells

    PMID:26439302

    Open questions at the time
    • nucleosomal (versus peptide) engagement not yet resolved at this stage
    • interplay between PZP reading and OM-LZ DOT1L binding not integrated
  12. 2017 High

    Demonstrated a non-leukemic developmental requirement, with Mllt10 knockout causing midline facial cleft through loss of Af10-dependent H3K79me at the AP2α locus.

    Evidence Mllt10 knockout mouse, ChIP for H3K79me at AP2α in nasal processes, and DOT1L-inhibitor phenocopy

    PMID:28931923

    Open questions at the time
    • other AF10-dependent developmental target genes not catalogued
    • tissue-specific targeting mechanism unexplained
  13. 2018 High

    Provided atomic detail of the AF10-DOT1L interface, solving the OM-LZ/DOT1L coiled-coil complex, showing zinc stabilization, and proving the interface is required for MLL-AF10 transformation.

    Evidence X-ray crystallography of AF10 OM-LZ alone and with DOT1L coiled-coil, interface mutagenesis, and leukemic transformation assay

    PMID:29563185

    Open questions at the time
    • functional role of zinc regulation in normal cells not defined
    • whether the interface is druggable in leukemia untested here
  14. 2021 High

    Integrated nucleosome-level PZP recognition, oncogenic JAK/STAT and Tip60 axes, and a reprogramming-barrier role, establishing AF10 as a multivalent chromatin reader controlling H3K79me-dependent cell identity and additional leukemogenic signaling.

    Evidence PZP-nucleosome crystallography with transformation rescue, BioID proteomics with reprogramming assays, and proteomics/genetic-pharmacological dissection of JAK1 and Tip60 in AML models

    PMID:33690798 PMID:33967269 PMID:34215314 PMID:34226546

    Open questions at the time
    • how JAK1 recruitment relates mechanistically to H3K79me deposition unclear
    • whether Tip60/H2A.Z acetylation acts upstream or in parallel to DOT1L unresolved
  15. 2023 High

    Showed AF10 governs the higher-order patterning of H3K79 methylation and Pol II distribution to maintain cell identity and, in testis, partners with DOT1L for histone-to-protamine replacement during spermiogenesis.

    Evidence AF10 CRISPR deletion with CUT&RUN/ChIP-seq for H3K79me1/2/3 and Pol II plus reprogramming assays; and testis co-IP, co-localization, and Mllt10 conditional knockout with sperm histone-retention readout

    PMID:37082953 PMID:37995701

    Open questions at the time
    • how AF10 selects which H3K79 methylation order to deposit at a given locus unknown
    • mechanism coupling H3K79me patterning to Pol II redistribution undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AF10's two chromatin-engaging modules (PZP nucleosome reading and OM-LZ DOT1L binding) are coordinated to choose specific loci and to set the order of H3K79 methylation, and how the non-DOT1L oncogenic activities (JAK1, Tip60, CRM1) are mechanistically integrated, remains unresolved.
  • no unified model linking PZP/OM-LZ engagement to locus selection
  • mechanism setting H3K79me1 vs me2/me3 at a locus unknown
  • integration of JAK/STAT, Tip60, and CRM1 axes with the DOT1L methyltransferase axis undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 3 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 3 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
CRM1/XPO1CTNNB1DOT1LGAS41INI1/SMARCB1JAK1KAT5/TIP60TCF4
Complex memberships
AF10-DOT1L complexSWI/SNF (proximity via GAS41/INI1)

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 AF10 protein contains a conserved cysteine-rich LAP/PHD zinc finger motif (now called LAP finger) that is proposed to be a DNA-binding domain; the LAP domain consensus sequence was defined by homology across 25+ proteins and the domain is disrupted in leukemia-associated chromosomal translocations. Sequence homology analysis and structural characterization of zinc finger motif Proceedings of the National Academy of Sciences of the United States of America Low 7568208
1995 In the t(10;11)(p12;q23) translocation causing AML, the leucine zipper motif of AF10 is consistently fused onto the N-terminal region of MLL/HRX, establishing that the leucine zipper of AF10 is a critical functional element juxtaposed onto MLL in all examined cases. Southern analysis and RT-PCR sequencing of leukemia patient samples Blood Medium 7662954
2000 AF10 contains an extended LAP/PHD finger domain that mediates homo-oligomerization of recombinant AF10 protein; AF10 also binds cruciform DNA via an AT-hook motif and is localized to the nucleus by a bipartite nuclear localization signal in its N-terminal region. Biochemical analysis of recombinant AF10 protein; GST pulldown for oligomerization; DNA-binding assay; subcellular fractionation Journal of molecular biology Medium 10860745
2001 AF10 interacts with the Drosophila heterochromatin protein HP1 (in vitro and in vivo), and the Drosophila AF10 homolog dAF10 functions in heterochromatin-dependent gene silencing (position effect variegation), placing it in the HP1-dependent silencing pathway. In vitro binding assay and co-immunoprecipitation (in vivo); genetic analysis of position effect variegation in Drosophila EMBO reports Medium 11266362
2002 The AF10 leucine zipper domain interacts with GAS41 (a glioblastoma amplified gene product homologous to yeast ANC1); GAS41 in turn co-immunoprecipitates with INI1 (SNF5/SWI-SNF component), and INI1 is present in AF10 immunoprecipitates, placing AF10 in proximity to the SWI/SNF chromatin remodeling complex. Yeast two-hybrid screen; co-immunoprecipitation (in vivo confirmation) Blood Medium 11756182
2002 The AF10 leucine zipper (comprising two adjacent alpha-helical domains, 82 aa) is necessary and sufficient for MLL-AF10-mediated myeloid immortalization and leukemic transformation; deletion of the 29-aa leucine zipper within this region completely abrogates transforming activity; the same minimal domain also confers transcriptional activation when fused to MLL or GAL4 DNA-binding domains. Structure-function analysis with retroviral transduction of deletion mutants into primary murine myeloid progenitors; serial replating assays; in vivo leukemia model; GAL4 transcriptional reporter assay Blood High 11986236
2001 AF10 physically interacts with the synovial sarcoma-associated protein SYT; the interaction was mapped to the N-terminal region of SYT and a C-terminal region of AF10 outside known functional domains; co-localization confirmed in transfected cells. Yeast two-hybrid screen; co-immunoprecipitation of endogenous and epitope-tagged proteins; co-localization by immunofluorescence; sequential deletion mapping Oncogene Medium 11423977
2003 The Drosophila AF10 homolog Alhambra (ALH) full-length protein has no activity on Polycomb group-responsive elements (PREs), but overexpression of the isolated leucine zipper domain activates several PREs; the PHD domain within the full-length protein inhibits the PRE-deregulating activity of the leucine zipper; this PRE deregulation is conserved in the human AF10 leucine zipper domain expressed in Drosophila. Drosophila genetics; PRE reporter assays; domain deletion/overexpression analysis in flies Molecular and cellular biology Medium 12482966
2006 CALM-AF10 fusion protein interacts with the H3K79 methyltransferase hDOT1L through the AF10 moiety; hDOT1L prevents nuclear export of CALM-AF10 and upregulates Hoxa5 through H3K79 methylation, contributing to leukemic transformation. Co-immunoprecipitation; ChIP for H3K79 methylation at Hoxa5 locus; retroviral bone marrow transformation assay; nuclear export assay Nature cell biology High 16921363
2006 The CALM-AF10 fusion protein alters subcellular localization of the lymphoid transcription factor Ikaros by coexpression; the AF10 leucine zipper domain is required for the AF10-Ikaros interaction; the transcriptional repressor activity of Ikaros is reduced by AF10. Yeast two-hybrid screen; GST pulldown; co-immunoprecipitation; immunofluorescence co-localization; transcriptional reporter assay Oncogene Medium 18037964
2006 A novel CALM-interacting protein, CATS, increases the nuclear (and specifically nucleolar) localization of both CALM and the leukemogenic CALM/AF10 fusion protein; the CATS interaction domain was mapped to aa 221-335 of CALM. Yeast two-hybrid screen; GST pulldown; co-immunoprecipitation; co-localization by fluorescence microscopy; domain mapping Oncogene Medium 16491119
2009 The CALM-AF10 fusion protein disrupts the normal AF10-mediated association of hDOT1L with chromatin, causing a global reduction of H3K79 methylation; cells with reduced H3K79 methylation show increased sensitivity to gamma-irradiation and chromosomal instability. ChIP analysis of H3K79 methylation; co-immunoprecipitation; gamma-irradiation sensitivity assays; cytogenetic analysis of leukemia patient samples Blood Medium 19443658
2010 MLLT10/AF10 and DOT1L are TCF4/β-catenin interactors in intestinal crypts; the AF10-DOT1L complex is recruited to Wnt target genes in a β-catenin-dependent manner and deposits H3K79 methylation over their coding regions; depletion of MLLT10/AF10 selectively impairs Wnt target gene expression and intestinal proliferation. Proteomics/mass spectrometry of TCF4/β-catenin complex; ChIP-H3K79me on Wnt target genes; siRNA knockdown with expression array; zebrafish morpholino experiments; genetic epistasis with apc-mutant zebrafish PLoS biology High 21103407
2011 For CALM-AF10 leukemia transformation, the clathrin-binding domain of CALM (C-terminal 248 aa) and the octapeptide motif-leucine zipper (OM-LZ) domain of AF10 are the minimal sufficient domains; this 'minimal fusion' retains aberrant Hoxa cluster upregulation characteristic of full-length CALM-AF10. Structure-function analysis with CALM and AF10 domain deletion mutants; colony-forming assays; in vivo mouse leukemia model; gene expression analysis Leukemia High 21681188
2011 Full-length CALM-AF10 localizes to the nucleus (not cytoplasm) in leukemia cells and has a propensity to homo-oligomerize as shown by FRET analysis; CALM-AF10 suppresses H3K79 methylation regardless of the presence of clathrin. Fluorescence microscopy; FRET analysis; ChIP for H3K79 methylation; mouse leukemia model with domain deletion constructs Oncogene Medium 21706055
2012 MLL-AF10 and CALM-AF10 mediated transformation is dependent on the H3K79 methyltransferase DOT1L; conditional Dot1l knockout abolishes in vitro transformation and in vivo leukemia initiation/maintenance; pharmacological DOT1L inhibition (EPZ004777) suppresses Hoxa cluster genes and Meis1, and selectively impairs proliferation of MLL-AF10 and CALM-AF10 transformed cells. Conditional Dot1l knockout mouse model; in vitro colony transformation assay; in vivo leukemia model; DOT1L inhibitor (EPZ004777) treatment; gene expression analysis Leukemia High 23138183
2012 The PHD1-PHD2 module of the C. elegans AF10 ortholog ZFP-1 is essential for viability; the first PHD finger contributes to preferential binding of the PHD1-PHD2 domain to H3K4-methylated histone H3 tails; ZFP-1 occupancy genome-wide peaks at H3K4me-enriched promoters of active genes, and H3K4 methylation is required for ZFP-1 localization to promoters in the embryo. Genetic analysis (C. elegans deletion mutants); biochemical histone-tail binding assays; ChIP-seq for ZFP-1 and H3K4me marks Molecular and cellular biology High 23263989
2013 The C. elegans AF10 homolog 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 increases H3K79 methylation and decreases H2B monoubiquitination (which promotes transcription), thereby negatively modulating Pol II elongation. Genomic (ChIP-seq, RNA-seq) and biochemical approaches; genetic knockdown; Pol II pausing analysis during development and stress response 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 in-frame with AF10 are sufficient to immortalize murine hematopoietic progenitors; the CALM NES is essential for Hoxa gene upregulation and aberrant H3K79 methylation by CALM-AF10, possibly through mislocalization of DOT1L. NES mutational analysis; retroviral transformation assay; ChIP for H3K79me and HOXA gene expression; Leptomycin B (CRM1 inhibitor) treatment; heterologous NES fusion constructs Blood High 23487024
2014 CRM1 physically localizes to HOXA loci and recruits CALM-AF10 to HOXA chromatin through the CALM NES-CRM1 interaction; genetic and pharmacological inhibition of CALM-CRM1 interaction prevents CALM-AF10 enrichment at HOXA chromatin and immediately abolishes HOXA transcription; CRM1 thus has a novel chromatin-binding and transcription factor-recruiting function. ChIP for CRM1 and CALM-AF10 at HOXA loci; genetic CALM NES mutants; CRM1 inhibitor treatment; transcriptional analysis Leukemia High 25027513
2015 The AF10 PZP domain (PHD finger-Zn knuckle-PHD finger module) reads unmodified H3K27; structural studies reveal that H3 binding triggers rearrangement of the PZP module to form an H3(22-27)-accommodating channel where unmodified H3K27 is encaged in a hydrogen-bond acceptor-lined cavity; H3K27 modification abrogates this interaction. In cells, PZP recognition of H3 is required for H3K79 dimethylation, expression of DOT1L-target genes, and proliferation of DOT1L-addicted leukemic cells. Crystal structure of PZP-H3 complex; mutagenesis of binding interface; histone peptide pulldowns; ChIP for H3K79me2 in cells with PZP mutants; cell proliferation assays Molecular cell High 26439302
2017 Mllt10 knockout mice exhibit midline facial cleft associated with reduced H3K79 methylation in nasal processes; AP2α expression is directly regulated by Af10-dependent H3K79me at its locus, and is specifically reduced in nasal processes of Mllt10-KO embryos; pharmacological suppression of H3K79me completely phenocopies Mllt10-KO. Mllt10 knockout mouse; ChIP for H3K79me at AP2α locus in nasal processes; DOT1L inhibitor treatment phenocopy experiment; gene expression analysis Scientific reports High 28931923
2018 Crystal structures of both apo AF10 OM-LZ and its complex with the coiled-coil domain of DOT1L were solved; disruption of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation; zinc stabilizes the DOT1L-AF10 complex and may regulate HOXA gene expression. X-ray crystallography of AF10 OM-LZ alone and in complex with DOT1L coiled-coil domain; interface mutagenesis; leukemic transformation assay Genes & development High 29563185
2021 AF10 fusions (PICALM-AF10 and MLL-AF10) directly recruit JAK1 kinase and activate a JAK/STAT-mediated inflammatory signaling cascade; genetic Jak1 deletion or pharmacological JAK/STAT inhibition elicits potent anti-oncogenic effects in mouse and human AF10-fusion AML models. Inducible mouse AML models; proteomics/protein interactome analysis; genetic Jak1 conditional knockout; pharmacological JAK/STAT inhibition; transcriptomic and epigenomic profiling Blood High 33690798
2021 The AF10 PZP domain (AF10PZP) binds the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA; AF10PZP associates with active chromatin marks and discriminates against H3K27me3; disruption of AF10PZP function in CALM-AF10 drives transformation, while incorporation of functional AF10PZP into CALM-AF10 prevents transformation, promotes nuclear localization, and downregulates Hoxa genes. Crystallography of AF10PZP-nucleosome complex; biochemical binding assays; mutagenesis; bone marrow transformation assays in vitro and in vivo; ChIP; gene expression analysis Nature communications High 34226546
2021 AF10 (MLLT10) is required for higher-order H3K79 methylation (H3K79me2/me3) in somatic cells; suppression of AF10 via RNAi or CRISPR/Cas9 significantly increases somatic cell reprogramming efficiency; re-expression of wild-type AF10 but not a DOT1L-binding-impaired AF10 mutant rescues H3K79 methylation and reduces reprogramming efficiency, establishing AF10 as a barrier to reprogramming through its regulation of DOT1L-dependent H3K79 methylation. Proximity-based labeling proteomics (BioID); RNAi and CRISPR/Cas9 knockdown; reprogramming efficiency assay; rescue with wild-type vs. DOT1L-binding mutant AF10; H3K79me western blot; transcriptomic analysis Epigenetics & chromatin High 34215314
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. ChIP showing Tip60 recruitment to Hoxa9 by MLL-AF10; H2A.Z acetylation assay; conditional Tip60 knockout; leukemia development assay in mice Leukemia High 33967269
2023 DOT1L associates with MLLT10 in testis; DOT1L and MLLT10 co-localize to sex chromatin in meiotic and post-meiotic germ cells in an inter-dependent manner; both DOT1L and MLLT10 are essential for H3K79me2 in germ cells and for histone-to-protamine replacement during spermiogenesis; loss of either DOT1L or MLLT10 results in histone retention in sperm and male subfertility. Co-immunoprecipitation (DOT1L-MLLT10 in testis); immunofluorescence co-localization in germ cells; Mllt10 conditional knockout mouse; H3K79me2 ChIP/immunostaining; sperm histone retention assay Development (Cambridge, England) High 37082953
2023 AF10 deletion evicts H3K79me2/3 from gene bodies and redistributes H3K79me1 to transcription start sites; AF10 loss also redistributes RNA Pol II to a pattern characteristic of pluripotency at highly expressed housekeeping genes, facilitating iPSC formation without major steady-state transcriptional changes; this reveals that AF10 controls the patterning of H3K79 methylation orders to maintain cell identity. AF10 genetic deletion (CRISPR); CUT&RUN/ChIP for H3K79me1/me2/me3; RNA Pol II ChIP-seq; reprogramming efficiency assay; DOT1L chemical inhibition as comparison Stem cell reports High 37995701
2007 The nuclear form of FLRG (follistatin-related gene) interacts with AF10 via the N-terminal PHD-containing region of AF10; FLRG enhances AF10 homo-oligomerization and augments the transcriptional activation properties of AF10 in reporter assays. Yeast two-hybrid screen; far-Western blot; co-immunoprecipitation; transcriptional reporter (Gal4-AF10 fusion); domain mapping Biology of the cell Medium 17868029

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 268 8643484
2006 Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L. Nature cell biology 147 16921363
1995 The leukemia-associated-protein (LAP) domain, a cysteine-rich motif, is present in a wide range of proteins, including MLL, AF10, and MLLT6 proteins. Proceedings of the National Academy of Sciences of the United States of America 137 7568208
1995 The t(10;11) translocation in acute myeloid leukemia (M5) consistently fuses the leucine zipper motif of AF10 onto the HRX gene. Blood 115 7662954
2012 Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l. Leukemia 114 23138183
2003 CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCRgammadelta lineage. Blood 114 12676784
2002 The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10. Blood 112 11986236
2006 Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia. Cancer cell 99 17097559
1995 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. Cancer research 79 7671224
2002 The MLL fusion partner AF10 binds GAS41, a protein that interacts with the human SWI/SNF complex. Blood 76 11756182
2010 The leukemia-associated Mllt10/Af10-Dot1l are Tcf4/β-catenin coactivators essential for intestinal homeostasis. PLoS biology 75 21103407
2000 Molecular analysis of the CALM/AF10 fusion: identical rearrangements in acute myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma patients. Leukemia 72 10637482
1993 Recombinant IL-6 activates p42 and p44 mitogen-activated protein kinases in the IL-6 responsive B cell line, AF-10. Journal of immunology (Baltimore, Md. : 1950) 72 8388418
2015 The PZP Domain of AF10 Senses Unmodified H3K27 to Regulate DOT1L-Mediated Methylation of H3K79. Molecular cell 68 26439302
2007 The role of CALM-AF10 gene fusion in acute leukemia. Leukemia 64 18094714
2000 Biochemical analyses of the AF10 protein: the extended LAP/PHD-finger mediates oligomerisation. Journal of molecular biology 64 10860745
2007 Expression of a CALM-AF10 fusion gene leads to Hoxa cluster overexpression and acute leukemia in transgenic mice. Cancer research 59 17804713
2013 New MLLT10 gene recombinations in pediatric T-acute lymphoblastic leukemia. Blood 55 23673860
1999 Consistent detection of CALM-AF10 chimaeric transcripts in haematological malignancies with t(10;11)(p13;q14) and identification of novel transcripts. British journal of haematology 51 10554802
2009 Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10-positive leukemias. Blood 50 19443658
2006 The novel CALM interactor CATS influences the subcellular localization of the leukemogenic fusion protein CALM/AF10. Oncogene 50 16491119
2013 The ZFP-1(AF10)/DOT-1 complex opposes H2B ubiquitination to reduce Pol II transcription. Molecular cell 46 23806335
2012 PICALM-MLLT10 acute myeloid leukemia: a French cohort of 18 patients. Leukemia research 45 22871473
1999 Mixed-lineage leukemia with t(10;11)(p13;q21): an analysis of AF10-CALM and CALM-AF10 fusion mRNAs and clinical features. Genes, chromosomes & cancer 42 10221337
2001 The synovial sarcoma associated protein SYT interacts with the acute leukemia associated protein AF10. Oncogene 41 11423977
2014 A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias. Leukemia 39 25027513
2011 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. Leukemia 38 22064352
2008 The CALM and CALM/AF10 interactor CATS is a marker for proliferation. Molecular oncology 38 19383357
2011 The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice. Leukemia 33 21681188
2013 A CALM-derived nuclear export signal is essential for CALM-AF10-mediated leukemogenesis. Blood 31 23487024
2007 The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros. Oncogene 31 18037964
1996 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). Blood 30 8896421
2019 Acute leukemias harboring KMT2A/MLLT10 fusion: a 10-year experience from a single genomics laboratory. Genes, chromosomes & cancer 27 30707474
2013 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. International journal of cancer 27 23564351
2003 The leucine zipper motif of the Drosophila AF10 homologue can inhibit PRE-mediated repression: implications for leukemogenic activity of human MLL-AF10 fusions. Molecular and cellular biology 27 12482966
1998 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. Leukemia 25 9737689
2001 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. Genes, chromosomes & cancer 24 11477655
2010 Acute leukemia with PICALM-MLLT10 fusion gene: diagnostic and treatment struggle. Cancer genetics and cytogenetics 23 20875875
2004 Purification and characterization of inulinase from Aspergillus niger AF10 expressed in Pichia pastoris. Protein expression and purification 23 15135402
2001 The Drosophila homolog of the human AF10 is an HP1-interacting suppressor of position effect variegation. EMBO reports 23 11266362
1998 Expression pattern and cellular distribution of the murine homologue of AF10. Biochimica et biophysica acta 22 9878787
2020 miR-331-3p Inhibits Tumor Cell Proliferation, Metastasis, Invasion by Targeting MLLT10 in Non-Small Cell Lung Cancer. Cancer management and research 21 32765078
2018 Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis. Genes & development 21 29563185
2003 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. Cancer genetics and cytogenetics 20 12810254
1999 The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene. Oncogene 19 10602503
2020 The Association of the Copy Number Variation of the MLLT10 Gene with Growth Traits of Chinese Cattle. Animals : an open access journal from MDPI 18 32033330
2009 Retroviral insertional mutagenesis identifies Zeb2 activation as a novel leukemogenic collaborating event in CALM-AF10 transgenic mice. Blood 18 20007546
2001 Molecular analysis of the genomic inversion and insertion of AF10 into MLL suggests a single-step event. Genes, chromosomes & cancer 17 11135434
2021 Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia. Leukemia 16 33967269
2019 Acute myeloid leukemia driven by the CALM-AF10 fusion gene is dependent on BMI1. Experimental hematology 16 31022428
2021 A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML. Blood 15 33690798
2021 The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations. Nature communications 14 34226546
2006 A case of acute myelogenous leukemia with MLL-AF10 fusion caused by insertion of 5' MLL into 10p12, with concurrent 3' MLL deletion. Cancer genetics and cytogenetics 14 17074587
2001 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. Mechanisms of development 14 11165485
1998 Interstitial insertion of AF10 into the ALL1 gene in a case of infant acute lymphoblastic leukemia. Cancer genetics and cytogenetics 14 9844603
2021 AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation. Epigenetics & chromatin 13 34215314
2011 The clathrin-binding domain of CALM-AF10 alters the phenotype of myeloid neoplasms in mice. Oncogene 13 21706055
2004 MLL-MLLT10 fusion in acute monoblastic leukemia: variant complex rearrangements and 11q proximal breakpoint heterogeneity. Cancer genetics and cytogenetics 13 15262427
2001 Identification and molecular characterisation of a CALM-AF10 fusion in acute megakaryoblastic leukaemia. Leukemia 13 11417476
1997 A novel MLL-AF10 fusion mRNA variant in a patient with acute myeloid leukemia detected by a new asymmetric reverse transcription PCR method. Leukemia 13 9305618
2012 The conserved PHD1-PHD2 domain of ZFP-1/AF10 is a discrete functional module essential for viability in Caenorhabditis elegans. Molecular and cellular biology 12 23263989
2005 MLL-MLLT10 fusion gene in pediatric acute megakaryoblastic leukemia. Leukemia research 12 16111539
2005 Cryptic MLL-AF10 fusion caused by insertion of duplicated 5' part of MLL into 10p12 in acute leukemia: a case report. Cancer genetics and cytogenetics 12 16213369
2002 Incidence of MLL rearrangement in acute myeloid leukemia, and a CALM-AF10 fusion in M4 type acute myeloblastic leukemia. Leukemia & lymphoma 12 11911106
2024 Structural variants involving MLLT10 fusion are associated with adverse outcomes in pediatric acute myeloid leukemia. Blood advances 11 38306602
2022 Pleiotropic MLLT10 variation confers risk of meningioma and estrogen-mediated cancers. Neuro-oncology advances 11 35702670
2017 Mllt10 knockout mouse model reveals critical role of Af10-dependent H3K79 methylation in midfacial development. Scientific reports 11 28931923
2015 The target cell of transformation is distinct from the leukemia stem cell in murine CALM/AF10 leukemia models. Leukemia 11 26686248
2007 AF10-dependent transcription is enhanced by its interaction with FLRG. Biology of the cell 11 17868029
2000 CALM-AF10 fusion gene in leukemias: simple and inversion-associated translocation (10;11). Cancer genetics and cytogenetics 11 11106826
2000 Protean clinical manifestations in children with leukemias containing MLL-AF10 fusion. Leukemia 11 11187895
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2018 Dysregulated transcriptional networks in KMT2A- and MLLT10-rearranged T-ALL. Biomarker research 10 30159143
2016 Cooperation of MLL/AF10(OM-LZ) with PTPN11 activating mutation induced monocytic leukemia with a shorter latency in a mouse bone marrow transplantation model. International journal of cancer 10 27859216
2014 Nuclear export signal within CALM is necessary for CALM-AF10-induced leukemia. Cancer science 10 24397609
2010 MLL/AF10(OM-LZ)-immortalized cells expressed cytokines and induced host cell proliferation in a mouse bone marrow transplantation model. International journal of cancer 10 19711340
2010 Clathrin assembly lymphoid myeloid leukemia-AF10-positive acute leukemias: a report of 2 cases with a review of the literature. The Korean journal of laboratory medicine 10 20445327
2003 Monocytic leukemia with CALM/AF10 rearrangement showing mediastinal emphysema. American journal of hematology 10 12555219
2020 MLLT10 in benign and malignant hematopoiesis. Experimental hematology 9 32569758
2018 Mediastinal Myeloid Sarcoma with TP53 Mutation Preceding Acute Myeloid Leukemia with a PICALM-MLLT10 Fusion Gene. Acta haematologica 9 30227397
2023 Cryptic KMT2A/MLLT10 fusion detected by next-generation sequencing in a case of pediatric acute megakaryoblastic leukemia. Cancer genetics 8 37478796
2020 Failure of tofacitinib to achieve an objective response in a DDX3X-MLLT10 T-lymphoblastic leukemia with activating JAK3 mutations. Cold Spring Harbor molecular case studies 8 32843425
2023 The DOT1L-MLLT10 complex regulates male fertility and promotes histone removal during spermiogenesis. Development (Cambridge, England) 7 37082953
2022 Broad genomic workup including optical genome mapping uncovers a DDX3X: MLLT10 gene fusion in acute myeloid leukemia. Frontiers in oncology 7 36158701
2019 Molecular and phenotypic characterization of an early T-cell precursor acute lymphoblastic lymphoma harboring PICALM-MLLT10 fusion with aberrant expression of B-cell antigens. Cancer genetics 7 31739126
2014 Neuronal migration is regulated by endogenous RNAi and chromatin-binding factor ZFP-1/AF10 in Caenorhabditis elegans. Genetics 7 24558261
2014 Characterization and inhibition of AF10-mediated interaction. Journal of peptide science : an official publication of the European Peptide Society 7 24692230
2024 PICALM::MLLT10 may indicate a new subgroup of acute leukemias with miscellaneous immunophenotype and poor initial treatment response but showing sensitivity to venetoclax. EJHaem 6 38895061
2024 Clinicopathologic features and outcomes of acute leukemia harboring PICALM::MLLT10 fusion. Human pathology 6 38971327
2014 Effects of iron depletion on CALM-AF10 leukemias. Experimental hematology 6 25193880
1998 A human B cell line AF10 expressing HIL-17. Biochemistry and molecular biology international 6 9762409
1993 Interferon-alpha and dexamethasone effect on AF10 myeloma cell line sialytransferase activity. Biochemical medicine and metabolic biology 6 8373639
2023 Unexpected appearance of KMT2A::MLLT10 fusion transcript in acute myeloid leukemia with t(5;11)(q31;q23.3). Cancer genetics 5 36774707
2023 DOT1L interaction partner AF10 controls patterning of H3K79 methylation and RNA polymerase II to maintain cell identity. Stem cell reports 5 37995701
2017 Molecular studies reveal MLL-MLLT10/AF10 and ARID5B-MLL gene fusions displaced in a case of infantile acute lymphoblastic leukemia with complex karyotype. Oncology letters 5 28781666
2016 Transient spontaneous remission in congenital MLL-AF10 rearranged acute myeloid leukemia presenting with cardiorespiratory failure and meconium ileus. Molecular and cellular pediatrics 5 27510896
2014 MLLT10 and IL3 rearrangement together with a complex four-way translocation and trisomy 4 in a patient with early T-cell precursor acute lymphoblastic leukemia: A case report. Oncology reports 5 25435396
2006 Acute monocytic leukemia with coexpression of minor BCR-ABL1 and PICALM-MLLT10 fusion genes along with overexpression of HOXA9. Genes, chromosomes & cancer 5 16518848
2004 Molecular genetics of the Alhambra (Drosophila AF10) complex locus of Drosophila. Molecular genetics and genomics : MGG 5 15258852
1996 Gene BR140, which is related to AF10 and AF17, maps to chromosome band 3p25. Genes, chromosomes & cancer 5 8946209

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