Affinage

MLLT3

Protein AF-9 · UniProt P42568

Length
568 aa
Mass
63.4 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

MLLT3 (AF9) is a chromatin-associated transcriptional regulator that couples histone acylation readout to H3K79 methylation and transcriptional elongation, governing cell-fate decisions in development, hematopoiesis, and cancer (PMID:25417107, PMID:31776511). Its N-terminal YEATS domain reads histone H3 acylation through an immunoglobulin-fold aromatic 'sandwiching' cage, binding H3K9ac (and to a lesser extent H3K27ac/H3K18ac) and binding crotonyllysine with even higher affinity via Phe59/Tyr78-mediated π-aromatic stacking, a recognition mode distinct from bromodomains (PMID:25417107, PMID:27105114, PMID:27545619). Chromatin engagement by the YEATS domain recruits the H3K79 methyltransferase DOT1L, and the degree of DOT1L recruitment scales directly with downstream H3K79me2/3 deposition and biological output (PMID:25417107, PMID:25921540). The C-terminal AHD domain is intrinsically disordered and folds upon binding partner proteins AF4, DOT1L, BCOR, and CBX8 in a mutually exclusive manner, allowing AF9 to assemble distinct effector complexes (PMID:32954361, PMID:34174329). Through the Dot1a–Af9 axis, AF9 binds defined promoter elements and represses target genes including ENaCalpha, endothelin-1, and Tbr1 via H3K79 methylation, with the ENaCalpha repression being relieved by aldosterone signaling, by Sgk1-mediated phosphorylation of Af9, and by AF17-driven nuclear export of Dot1a (PMID:16636056, PMID:17332896, PMID:19864429, PMID:23152297, PMID:20348416, PMID:23077601). In hematopoietic stem cells MLLT3 acts as an essential maintenance factor that localizes to active promoters, sustains H3K79me2, and protects the HSC transcriptional program, enabling ex vivo HSC expansion (PMID:31776511). As the MLL-AF9 fusion oncoprotein, AF9 constitutively recruits the EAP/super-elongation complex—including DOT1L, P-TEFb (CDK9/Cyclin T), and CBX8/BCOR—to HOX loci to drive leukemic transformation, and disrupting individual AHD partner interactions (DOT1L, BCOR, CBX8) selectively abrogates leukemogenesis while sparing normal hematopoiesis (PMID:25921540, PMID:20854876, PMID:22094252, PMID:32954361, PMID:35245435, PMID:33562706). AF9 also functions context-dependently as a coactivator, recruiting TET2 to neurodevelopmental loci, partnering with RAR/P-TEFb at retinoid-regulated genes, and activating gluconeogenic genes via H3K9ac in colorectal cancer (PMID:27462416, PMID:23762261, PMID:37565737).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 Low

    Before AF9's biochemical role was clear, ortholog analysis placed it within chromatin-remodeling and transcription machinery, framing it as a general transcription/chromatin factor.

    Evidence Biochemical purification and interaction blots of the yeast ortholog TFG3/ANC1 with SWI/SNF and TFIID/TFIIF

    PMID:8668146

    Open questions at the time
    • Inference about human AF9 is indirect from yeast
    • No direct demonstration of human AF9 in SWI/SNF
  2. 2002 High

    Genetic ablation established AF9 as a physiological regulator of Hox gene expression and axial patterning in vivo, but unexpectedly dispensable for embryonic hematopoiesis.

    Evidence Af9 null mouse with skeletal analysis and in situ hybridization of Hoxd4

    PMID:12242306

    Open questions at the time
    • Molecular mechanism linking AF9 to Hox regulation not resolved here
    • Did not address adult HSC requirement
  3. 2006 High

    Identified the Dot1a–AF9 complex as a hormone-regulated repressor module, answering how AF9 directs site-specific H3K79 methylation and gene repression.

    Evidence Reciprocal co-IP, co-localization, ChIP, luciferase reporter and RNAi in renal collecting duct cells

    PMID:16636056

    Open questions at the time
    • Did not define how AF9 is targeted to the promoter
    • Generality beyond ENaCalpha unknown at the time
  4. 2007 High

    Established a signaling input to the complex by showing Sgk1 phosphorylation of Af9 disrupts the Dot1a interaction, connecting aldosterone/kinase signaling to chromatin state.

    Evidence Kinase assay, co-IP, ChIP, and Sgk1 knockout mice

    PMID:17332896

    Open questions at the time
    • Phosphosite mapping detail limited
    • Whether other AF9 functions are phosphoregulated unknown
  5. 2009 High

    Defined a regulatory mechanism in which AF17 competes for Dot1a and drives its nuclear export, controlling the availability of the Dot1a–AF9 repressive complex.

    Evidence Competitive binding, overexpression, leptomycin B inhibition, reporter and patch-clamp assays

    PMID:19864429

    Open questions at the time
    • Physiological trigger for AF17 competition unclear
    • Relevance to non-renal tissues untested
  6. 2012 High

    Demonstrated AF9 can bind DNA directly at a defined promoter element to recruit Dot1a, addressing how the complex achieves locus specificity, and extended repression to endothelin-1.

    Evidence EMSA, ChIP, promoter-deletion reporters, and conditional Dot1l knockout mice; ChIP and pharmacology for endothelin-1

    PMID:23077601 PMID:23152297

    Open questions at the time
    • Sequence specificity determinants of AF9 DNA binding not fully defined
    • Direct vs indirect DNA contact mechanism limited
  7. 2014 High

    Solved how AF9 reads chromatin by defining the YEATS domain as an acetyllysine reader using an aromatic sandwiching cage, mechanistically linking AF9 recruitment to DOT1L.

    Evidence Crystal structure, ChIP-seq genome-wide co-localization with H3K9ac, and in vitro binding assays

    PMID:25417107

    Open questions at the time
    • Did not establish full acylation repertoire
    • Quantitative contribution of reader vs DNA binding to targeting unresolved
  8. 2016 High

    Expanded the reader function by showing the YEATS domain prefers crotonyllysine over acetyllysine, linking a distinct histone acylation mark to active transcription.

    Evidence Crystal/NMR structures, mutagenesis of Phe59/Tyr78, and cell-based reporter/co-localization assays

    PMID:27105114 PMID:27545619

    Open questions at the time
    • In vivo physiological role of crotonyl reading not isolated from acetyl reading
    • Genome-wide crotonylation targets not mapped
  9. 2015 High

    Quantitatively connected DOT1L recruitment via three AF9-binding sites to H3K79 methylation dosage and to MLL-AF9 transformation potential.

    Evidence NMR structure of DOT1L-AF9 complex, structure-guided graded mutations, ChIP-seq, and transformation assays

    PMID:25921540

    Open questions at the time
    • Did not address other AHD partners
    • Therapeutic targetability of the interface not tested here
  10. 2010 Medium

    Characterized the leukemogenic EAP/elongation complex assembled on the AF9 C-terminus, explaining how MLL-AF9 sustains HOX expression during differentiation.

    Evidence Immunopurification, mass spectrometry, and ChIP-qPCR at Hoxa9/Meis1; ChIP and knockout for Tbr1 in cortex

    PMID:20348416 PMID:20854876

    Open questions at the time
    • Stoichiometry and architecture of EAP not defined
    • Single-lab interactome
  11. 2011 High

    Identified CBX8 as a partner specifically required for MLL-AF9 oncogenic HOX activation but dispensable for normal hematopoiesis, exposing a context-selective dependency.

    Evidence Co-IP, point mutagenesis, mouse leukemia model, and gene expression analysis; Cbx8 knockout mice

    PMID:22094252

    Open questions at the time
    • Mechanism by which CBX8 enables activation rather than Polycomb repression unclear
    • Did not resolve mutual exclusivity with other partners
  12. 2019 High

    Established MLLT3 as an essential HSC maintenance factor that sustains H3K79me2 and the stem-cell transcriptional program, enabling functional ex vivo HSC expansion.

    Evidence shRNA knockdown, lentiviral overexpression, xenotransplantation, and ChIP-seq in human HSPCs

    PMID:31776511

    Open questions at the time
    • Direct target genes mediating maintenance not fully resolved
    • Relationship to YEATS reader specificity in HSCs untested
  13. 2020 High

    Defined the structural logic of AHD partner selection, showing AF4/DOT1L/BCOR/CBX8 bind mutually exclusively and that disrupting BCOR binding selectively abolishes leukemogenesis.

    Evidence Crystal structures of AHD-CBX8 and AHD-BCOR, structure-guided mutagenesis, mouse leukemia model; NMR coupled folding/dynamics

    PMID:32954361 PMID:34174329

    Open questions at the time
    • How the disordered AHD partitions among partners in vivo unclear
    • Differential roles of each partner across cell types incomplete
  14. 2022 High

    Resolved the kinetics of MLL-AF9 action, showing it primarily drives transcriptional elongation at a core target set, and that combined DOT1L/MENIN inhibition phenocopies its loss.

    Evidence Auxin-inducible degron with kinetic ChIP-seq/RNA-seq and small-molecule inhibitors; engineered DOT1L PPI-mutant cells with transplantation

    PMID:33562706 PMID:35245435

    Open questions at the time
    • Primary direct targets vs secondary effects still being parsed
    • Why a subset of targets is hyper-dependent unknown
  15. 2021 Medium

    Provided pharmacological proof that YEATS-domain reader inhibition suppresses leukemic oncogene expression, validating the reader function as a drug target.

    Evidence Biochemical YEATS inhibition (SR-0813) and cell-based gene expression/PROTAC degradation in AML

    PMID:34079898

    Open questions at the time
    • In vivo efficacy and selectivity over ENL not fully established
    • Single study
  16. 2023 Medium

    Extended AF9's role beyond elongation and repression to context-dependent gene activation in solid tumors and stem-cell differentiation, including TET2 recruitment, RAR coactivation, and H3K9ac-driven gluconeogenic gene activation.

    Evidence Co-IP/MS, ChIP, epigenomic profiling, knockdown and mouse models across hESC neural differentiation, P19 cells, colorectal and breast cancer, and oral SCC

    PMID:18371451 PMID:23762261 PMID:27462416 PMID:31273053 PMID:33221433 PMID:37565737

    Open questions at the time
    • Whether activation vs repression is dictated by partner choice or chromatin context unresolved
    • Mostly single-lab studies per cancer type

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how AF9 switches between repressive (Dot1a-mediated) and activating outputs, and what determines partner selection by the disordered AHD in different cellular contexts.
  • No unified model of context-dependent activation vs repression
  • In vivo dynamics of AHD partner exchange not measured
  • How YEATS reader specificity is tuned across tissues unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0042393 histone binding 3 GO:0060090 molecular adaptor activity 3 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-4839726 Chromatin organization 3
Partners
AF17AF4BCORCBX8CDK9DOT1LRARTET2
Complex memberships
Dot1a-AF9 complexEAP/super-elongation complex (P-TEFb, DOT1L)MLL-AF9 fusion oncoprotein complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 The AF9 YEATS domain binds histone H3K9 acetylation (and to a lesser extent H3K27ac and H3K18ac) via a serine-lined aromatic 'sandwiching' cage (eight-stranded immunoglobulin fold), representing a novel acetyllysine-recognition mechanism distinct from bromodomains. ChIP-seq demonstrated genome-wide co-localization of AF9 with H3K9ac, and this chromatin recruitment of AF9 is important for recruitment of the H3K79 methyltransferase DOT1L. Crystal structure, ChIP-seq, in vitro binding assays Cell High 25417107
2016 The AF9 YEATS domain binds crotonyllysine with selectively higher affinity than acetyllysine. Structural studies revealed an extended aromatic sandwiching cage with π-aromatic and hydrophobic interactions specific to the crotonyl group; key residues Phe59 and Tyr78 were confirmed by mutagenesis. Cell-based experiments showed AF9 co-localizes with crotonylated H3 and positively regulates gene expression in a YEATS domain-dependent manner, directly linking histone crotonylation to active transcription. Crystal structure, NMR, mutagenesis, cell-based reporter and co-localization assays Molecular cell High 27105114 27545619
2016 NMR structural analysis of the AF9 YEATS domain bound to crotonyl-H3K18 revealed that the crotonyl carbonyl oxygen forms a hydrogen bond with backbone amide of Tyr78, and the double-bond side chain engages π-π aromatic stacking; mutational analysis confirmed Phe59 and Tyr78 as key recognition residues for crotonyllysine. NMR structure, mutagenesis, peptide binding assays Structure High 27545619
2015 DOT1L has three AF9-binding sites. NMR solution structure of a DOT1L-AF9 complex was determined. Structure-guided point mutations produced graded reductions in DOT1L recruitment to MLL-AF9, resulting in differential, dose-dependent loss of H3K79me2 and H3K79me3 at MLL-AF9 target genes; the degree of DOT1L recruitment directly correlated with MLL-AF9 hematopoietic transformation potential. NMR structure, mutagenesis, ChIP-seq, transformation assays Cell reports High 25921540
2006 AF9 and DOT1L (Dot1a) interact in vitro and in vivo and co-localize in the nuclei of renal collecting duct cells. Overexpression of AF9 results in histone H3K79 hypermethylation at the ENaCalpha promoter and repression of ENaCalpha transcription; AF9 knockdown has the opposite effect. Aldosterone negatively regulates AF9 expression, thereby relieving Dot1a-AF9-mediated H3K79 methylation and transcriptional repression. Co-IP, co-localization, ChIP, luciferase reporter, RNA interference, overexpression The Journal of biological chemistry High 16636056
2007 Sgk1 phosphorylates Af9, impairing the Dot1a-Af9 interaction and leading to targeted H3K79 hypomethylation at the ENaCalpha promoter and derepression of ENaCalpha transcription. This was demonstrated in renal collecting duct cells and in Sgk1 knockout mice, identifying Af9 as a physiologic substrate of Sgk1. Kinase assay, co-IP, ChIP, knockout mouse model The Journal of clinical investigation High 17332896
2009 AF17 and AF9 competitively bind to the same domain of Dot1a. Overexpression of AF17 redirects Dot1a from the nucleus to the cytoplasm, reducing H3K79 methylation and relieving Dot1a-AF9-mediated repression of alpha-ENaC. Nuclear export inhibitor leptomycin B blocked AF17-induced H3K79 hypomethylation, confirming the mechanism involves nuclear export of Dot1a. Competitive binding assays, overexpression, nuclear export inhibitor, luciferase reporter, patch clamp The Journal of biological chemistry High 19864429
2012 Af9 directly binds to the +78/+92 element of the ENaCalpha promoter (DNA-binding activity demonstrated by gel shift and antibody competition assays), recruiting Dot1a to mediate H3K79 dimethylation and transcriptional repression. Deletion of this element greatly reduced association of both Af9 and Dot1a. In vivo, collecting duct-specific Dot1l knockout mice showed elevated ENaCalpha mRNA, confirming the repression mechanism. Gel shift (EMSA), ChIP, promoter-deletion reporter assays, conditional knockout mouse American journal of physiology. Renal physiology High 23152297
2004 AF9 and AF4 interact at discrete subnuclear foci (designated 'AF4 bodies'). This interaction is maintained by the MLL-AF4 fusion protein, and expression of MLL-AF4 can alter the subnuclear localization of AF9. Co-IP, subnuclear co-localization/immunofluorescence Leukemia Medium 14603337
2003 AF9 binds specific isoforms of the BCL-6 corepressor (BCoR) through its carboxy-terminus; only BCoR isoforms containing a unique 34-aa sequence interact with AF9. BCoR isoforms that bind AF9 suppress AF9 transcriptional activation activity in reporter assays, whereas nonbinding isoforms do not. In vitro binding assays, co-IP, reporter gene assays Oncogene Medium 12776190
2001 The Polycomb group protein MPc3 interacts with the carboxy-terminus of AF9 (the same region fused to MLL in t(9;11) leukemia). The AF9-binding site on MPc3 maps to a central, non-conserved region distinct from RING1-binding motifs. The related Pc protein M33 does not interact with AF9. Protein interaction blots, co-IP Oncogene Low 11439343
2010 The C-terminal 90-amino-acid transforming domain of AF9 associates with multiple MLL translocation partners including ENL, AF4, LAF4, AF5q31, ELL, AF10, the RNA pol II CTD kinase CDK9/Cyclin T1/T2 (pTEFb), and the H3K79 methyltransferase DOT1L, forming the elongation assisting proteins (EAP) complex. MLL-AF9 prevents dissociation of this complex from Hoxa9 and Meis1 loci during differentiation. Immunopurification, mass spectrometry, ChIP-qPCR Experimental hematology Medium 20854876
2019 MLLT3 is highly enriched in human fetal, neonatal, and adult hematopoietic stem cells (HSCs) but is downregulated in culture. Depletion of MLLT3 prevented maintenance of transplantable HSCs in culture. Stabilizing MLLT3 expression enabled >12-fold expansion of transplantable HSCs with multilineage reconstitution in primary and secondary recipients. Overexpressed MLLT3 localized to active promoters in HSPCs, sustained H3K79me2 levels, and protected the HSC transcriptional program, acting as an HSC maintenance factor that links histone reader and modifying activities. shRNA knockdown, lentiviral overexpression, xenotransplantation, ChIP-seq Nature High 31776511
2010 In the developing mouse cerebral cortex, AF9 associates with the transcriptional start site of Tbr1, mediates H3K79 dimethylation at the Tbr1 gene, and suppresses RNA polymerase II occupancy at Tbr1. This interaction depends on AF9's interaction with DOT1L. AF9 maintains TBR2-positive progenitors in the SVZ and suppresses TBR1-positive upper-layer neuron cell fate. Af9 null mice show increased TBR1 expression, cytoplasmic TBR1 re-localization, and elevated NR1 (NMDAR subunit) expression. ChIP, in situ hybridization, mouse knockout, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America Medium 20348416
2015 AF9 promotes hESC neural differentiation by recruiting TET2 to neurodevelopmental gene loci. AF9 and TET2 physically interact (co-IP from AF9-associated protein complex), co-localize in 5hmC-positive neurons, and upon binding to AAC-containing motifs, AF9 recruits TET2 to direct 5mC-to-5hmC conversion at neurodevelopmental gene promoters, leading to sequential activation of neural target genes. Co-IP/mass spectrometry, ChIP, bisulfite/5hmC sequencing, shRNA knockdown, overexpression Cell discovery Medium 27462416
2002 Genetic inactivation of murine Af9 causes perinatal lethality and anterior homeotic transformation of the axial skeleton with no effect on hematopoiesis. In situ hybridization showed posterior shifts in Hoxd4 expression in Af9 null embryos, placing Af9 upstream of Hox gene regulation in embryonic patterning. Gene knockout (null mutation), in situ hybridization, skeletal analysis Molecular and cellular biology High 12242306
2008 MLLT3 knockdown in human cord blood CD34+ cells reduces erythroid and megakaryocytic output, while forced MLLT3 expression promotes erythroid and megakaryocytic progenitor production. Mutant analysis showed this depends on MLLT3's transcriptional regulatory activity. Cross-regulatory interactions between MLLT3 and GATA-1 were identified by gene expression and cis-regulatory element analyses. shRNA knockdown, lentiviral overexpression, colony assays, gene expression profiling, cis-regulatory analysis Cell stem cell Medium 18371451
1996 The yeast protein TFG3/TAF30/ANC1, significantly similar to ENL and AF-9, is a component of both the SWI/SNF chromatin-remodeling complex and the TFIIF and TFIID transcription complexes. TFG3 interacts with the SNF5 component of SWI/SNF in protein interaction blots, suggesting AF-9 may similarly interact with SNF5 in the human SWI/SNF complex. Biochemical purification, protein interaction blots Molecular and cellular biology Low 8668146
2013 AF9 (MLLT3) functions as a transcriptional coactivator of nuclear retinoic acid receptors (RARs) via its association with P-TEFb. Mass spectrometry identified AF9 as a novel RAR-interacting protein. RAR binds to transcribed regions of retinoid-regulated genes in association with RNA Pol II and P-TEFb activity. AF9 knockdown selectively affected clusters of retinoid-regulated genes and impaired neural differentiation of P19 stem-like cells. Mass spectrometry, ChIP, siRNA knockdown, differentiation assay PloS one Medium 23762261
2009 Diversin (mammalian homolog of Drosophila Diego) translocates to the nucleus and interacts with AF9. AF9 strongly augments Diversin-driven activation of JNK-dependent gene expression in the nucleus; this augmentation requires nuclear Diversin. Both Diversin and AF9 independently block canonical Wnt signaling. Co-IP, nuclear localization/translocation assays, reporter gene assays Biochemical and biophysical research communications Low 19591803
2011 CBX8, a Polycomb Group protein, physically interacts with MLL-AF9 and is required for MLL-AF9-induced transcriptional activation of HOX genes and leukemogenesis. Specific point mutations in MLL-AF9 that disrupt the CBX8 interaction abrogate HOX gene upregulation and leukemic transformation. Cbx8-deficient mice are viable with no hematopoietic defects, indicating the CBX8-AF9 interaction is specifically required in the oncogenic context. Co-IP, point mutagenesis, mouse leukemia model, gene expression analysis Cancer cell High 22094252
2020 Crystal structures of AF9 (AHD domain) in complex with CBX8 and BCOR were determined. Binding of AF4, DOT1L, BCOR, and CBX8 to AF9 is mutually exclusive. Structure-guided point mutations selectively disrupting BCOR binding to MLL-AF9 abrogated leukemogenic potential in vivo, reduced EYA1 expression and c-Myc protein levels, and altered MYC-driven and SIX-regulated gene expression programs. Disruption of CBX8 binding had no impact on in vitro proliferation. Crystal structure, mutagenesis, mouse leukemia model, gene expression analysis Blood cancer discovery High 32954361
2021 The C-terminal AHD (ANC1 homology domain) of AF9/MLLT3 is intrinsically disordered and undergoes coupled binding and folding upon interaction with partner proteins AF4, DOT1L, BCOR, and CBX8. Backbone dynamics studies of these complexes suggest a role for dynamics in function. Inhibitors targeting the intrinsically disordered AHD interactions have been described. NMR backbone dynamics, structural studies of complexes Journal of molecular biology Medium 34174329
2012 The Dot1a-Af9 complex represses endothelin-1 transcription in renal cells in vitro and in vivo. Dot1l knockout in collecting duct cells impaired Dot1a-H3K79me2 association with the endothelin-1 promoter and upregulated endothelin-1 mRNA and protein. In diabetic rats, spironolactone increased Dot1a and Af9 expression, restoring their repressive activity on endothelin-1. ChIP, conditional knockout mouse, overexpression, siRNA, in vivo pharmacology PloS one Medium 23077601
2022 Rapid degradation of MLL::AF9 (using degron-based small molecule system) causes changes in transcriptional elongation within 15 minutes at a core subset of target genes, prior to loss of active chromatin landscape. Combined DOT1L and MENIN inhibition resembles MLL::AF9 degradation in its effects on occupancy and gene expression, while single-agent treatment has more modest effects on MLL::AF9 chromatin occupancy. Auxin-inducible degron, ChIP-seq, RNA-seq, small-molecule inhibitors Molecular cell High 35245435
2021 In MLL-AF9 leukemia cells engineered with a DOT1L mutant defective for AF9 binding, DOT1L recruitment to critical MLL-AF9 target genes is completely disrupted and leukemic cell growth is inhibited. In contrast, disruption of AF9-DOT1L interaction in non-leukemic hematopoiesis has no effect on hematopoietic function (WT and PPI-deficient DOT1L but not enzymatically inactive DOT1L rescued hematopoiesis), indicating the AF9-DOT1L interaction is dispensable for normal hematopoiesis but required for leukemia. Engineered DOT1L mutants, ChIP, cell growth assays, conditional knockout mouse, transplantation Cancers High 33562706
2021 SR-0813, a potent ENL/AF9 YEATS domain inhibitor (IC50 = 25 nM for both), inhibits binding of acylated histone peptides to the YEATS domain. YEATS domain inhibition selectively suppresses ENL target genes including HOXA9/10, MYB, MYC, and other leukemia proto-oncogenes in AML cells. Biochemical YEATS domain inhibition assay, cell-based gene expression, PROTAC degradation ACS central science Medium 34079898
2023 In colorectal cancer, AF9 upregulates expression of gluconeogenic genes PCK2 and FBP1 via H3K9ac-mediated transcriptional activation at their promoters. Loss of AF9 decreases H3K9ac at PCK2 and FBP1 promoters, reduces their expression, and promotes glycolysis and tumor growth. AF9 itself is targeted by miR-145 via its 3'UTR. siRNA knockdown, AOM/DSS mouse model, ChIP, RNA-seq, co-IP Clinical and translational medicine Medium 37565737
2020 In basal-like breast cancer, AF9 interacts with Snail (confirmed by tandem mass spectrometry Co-IP), hampering Snail transcriptional activity. AF9 recruits CBP or GCN5 to activate Snail promoter. Depletion of AF9 promotes EMT and metastasis, while AF9 overexpression suppresses invasion. miR-5694 targets AF9 mRNA to downregulate its expression. Mass spectrometry, Co-IP, siRNA knockdown, overexpression, mouse metastasis model Molecular therapy Medium 33221433
2019 In oral cavity squamous cell carcinoma, MLLT3 knockdown reduces cell migration and invasion. The invasion defect is rescued by double knockdown of MLLT3 and CITED4. MLLT3 is required for DOT1L-associated H3K79 hypermethylation at the CITED4 promoter to repress it, consequently dysregulating HIF-1α-mediated EMT genes (TWIST, MMP1, MMP2, VIM, CDH1). siRNA knockdown, ChIP, rescue experiments, invasion assays The oncologist Medium 31273053

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 1206 16862118
2006 Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer cell 486 17045204
2014 AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell 322 25417107
2016 Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain. Molecular cell 311 27105114
1997 Two acute monocytic leukemia (AML-M5a) cell lines (MOLM-13 and MOLM-14) with interclonal phenotypic heterogeneity showing MLL-AF9 fusion resulting from an occult chromosome insertion, ins(11;9)(q23;p22p23). Leukemia 203 9305600
2012 Polycomb repressive complex 2 is required for MLL-AF9 leukemia. Proceedings of the National Academy of Sciences of the United States of America 201 22396593
2010 MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer cell 200 20159607
2016 MLL-AF9 Expression in Hematopoietic Stem Cells Drives a Highly Invasive AML Expressing EMT-Related Genes Linked to Poor Outcome. Cancer cell 199 27344946
2008 Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells. Cancer cell 176 18455126
1999 The mll-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis. The EMBO journal 176 10393173
2009 Structure of the MLL CXXC domain-DNA complex and its functional role in MLL-AF9 leukemia. Nature structural & molecular biology 146 20010842
1996 TFG/TAF30/ANC1, a component of the yeast SWI/SNF complex that is similar to the leukemogenic proteins ENL and AF-9. Molecular and cellular biology 143 8668146
2006 Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCalpha in an aldosterone-sensitive manner. The Journal of biological chemistry 142 16636056
2011 CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer cell 137 22094252
2007 Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha. The Journal of clinical investigation 132 17332896
2019 MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment. Nature 130 31776511
1994 A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-4, AF-9 nor ENL. Oncogene 118 8134107
2003 Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia. Blood 107 14615372
2000 Inter-chromosomal recombination of Mll and Af9 genes mediated by cre-loxP in mouse development. EMBO reports 100 11265751
1993 MLLT3 gene on 9p22 involved in t(9;11) leukemia encodes a serine/proline rich protein homologous to MLLT1 on 19p13. Oncogene 99 8414510
2015 Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 Di- and tri-methylation on target genes and transformation potential. Cell reports 94 25921540
2007 MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment. Leukemia 90 17851551
2017 MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia. Oncogene 87 28114278
2016 Structural Insights into Histone Crotonyl-Lysine Recognition by the AF9 YEATS Domain. Structure (London, England : 1993) 85 27545619
2000 DNA structural properties of AF9 are similar to MLL and could act as recombination hot spots resulting in MLL/AF9 translocations and leukemogenesis. Human molecular genetics 79 10861294
2012 MLL-AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny. Leukemia 74 23178754
2004 MLL fusion partners AF4 and AF9 interact at subnuclear foci. Leukemia 74 14603337
2003 The mixed lineage leukemia fusion partner AF9 binds specific isoforms of the BCL-6 corepressor. Oncogene 74 12776190
2021 Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia. ACS central science 73 34079898
2016 MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C. The Journal of clinical investigation 72 26878175
2012 EVI1 is critical for the pathogenesis of a subset of MLL-AF9-rearranged AMLs. Blood 71 22553314
2001 The polycomb protein MPc3 interacts with AF9, an MLL fusion partner in t(9;11)(p22;q23) acute leukemias. Oncogene 68 11439343
1997 Identification of complex genomic breakpoint junctions in the t(9;11) MLL-AF9 fusion gene in acute leukemia. Genes, chromosomes & cancer 68 9331569
2010 MLL-AF9 and MLL-ENL alter the dynamic association of transcriptional regulators with genes critical for leukemia. Experimental hematology 67 20854876
2003 Differential activation of "social" and "solitary" variants of the Caenorhabditis elegans G protein-coupled receptor NPR-1 by its cognate ligand AF9. The Journal of biological chemistry 65 12821653
2002 Mouse Af9 is a controller of embryo patterning, like Mll, whose human homologue fuses with Af9 after chromosomal translocation in leukemia. Molecular and cellular biology 63 12242306
2003 Apoptotic stimuli initiate MLL-AF9 translocations that are transcribed in cells capable of division. Cancer research 59 12649202
2022 MLL::AF9 degradation induces rapid changes in transcriptional elongation and subsequent loss of an active chromatin landscape. Molecular cell 58 35245435
2011 Inhibition of Rac GTPase signaling and downstream prosurvival Bcl-2 proteins as combination targeted therapy in MLL-AF9 leukemia. Blood 58 21940819
2008 MLLT3 regulates early human erythroid and megakaryocytic cell fate. Cell stem cell 58 18371451
2010 Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex. Proceedings of the National Academy of Sciences of the United States of America 52 20348416
2000 Cytogenetic and molecular analysis of the acute monocytic leukemia cell line THP-1 with an MLL-AF9 translocation. Genes, chromosomes & cancer 52 11066077
2019 MLL-AF9 initiates transformation from fast-proliferating myeloid progenitors. Nature communications 46 31852898
2004 The synthetic peptide PFWT disrupts AF4-AF9 protein complexes and induces apoptosis in t(4;11) leukemia cells. Leukemia 45 15269783
2018 Discovery of a Selective Inhibitor for the YEATS Domains of ENL/AF9. SLAS discovery : advancing life sciences R & D 44 30359161
2009 AF17 competes with AF9 for binding to Dot1a to up-regulate transcription of epithelial Na+ channel alpha. The Journal of biological chemistry 44 19864429
2017 Histone Acetyltransferase Activity of MOF Is Required for MLL-AF9 Leukemogenesis. Cancer research 43 28202522
2017 Autophagy is dispensable for Kmt2a/Mll-Mllt3/Af9 AML maintenance and anti-leukemic effect of chloroquine. Autophagy 41 28282266
2017 miR-125b promotes MLL-AF9-driven murine acute myeloid leukemia involving a VEGFA-mediated non-cell-intrinsic mechanism. Blood 39 28053194
2018 Impact of elevated anti-apoptotic MCL-1 and BCL-2 on the development and treatment of MLL-AF9 AML in mice. Cell death and differentiation 38 30470795
2018 Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia. Cell reports 37 29320732
2013 The trithorax protein partner menin acts in tandem with EZH2 to suppress C/EBPα and differentiation in MLL-AF9 leukemia. Haematologica 37 23349306
2013 Reprogramming of MLL-AF9 leukemia cells into pluripotent stem cells. Leukemia 37 24150221
2021 The Intrinsically Disordered Proteins MLLT3 (AF9) and MLLT1 (ENL) - Multimodal Transcriptional Switches With Roles in Normal Hematopoiesis, MLL Fusion Leukemia, and Kidney Cancer. Journal of molecular biology 36 34174329
2016 Modeling BCR-ABL and MLL-AF9 leukemia in a human bone marrow-like scaffold-based xenograft model. Leukemia 35 27125308
2021 P2X7 promotes the progression of MLL-AF9 induced acute myeloid leukemia by upregulation of Pbx3. Haematologica 34 32165482
2020 CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia. Cell reports 34 32460032
2016 Loss of Dnmt3b accelerates MLL-AF9 leukemia progression. Leukemia 34 27133822
2013 The AAA+ ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis. Leukemia 32 23403462
2020 SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia. Oncogene 31 33037410
2013 miR-150 blocks MLL-AF9-associated leukemia through oncogene repression. Molecular cancer research : MCR 31 23604034
2014 RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes. Molecular cancer 30 24517546
2005 Loss-of-function mutation of the AF9/MLLT3 gene in a girl with neuromotor development delay, cerebellar ataxia, and epilepsy. Human genetics 28 16001262
2015 AF9 promotes hESC neural differentiation through recruiting TET2 to neurodevelopmental gene loci for methylcytosine hydroxylation. Cell discovery 27 27462416
2018 Peptidomimetics for Targeting Protein-Protein Interactions between DOT1L and MLL Oncofusion Proteins AF9 and ENL. ACS medicinal chemistry letters 26 30258537
2020 BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity. Blood cancer discovery 25 32954361
2016 Rheb1 promotes tumor progression through mTORC1 in MLL-AF9-initiated murine acute myeloid leukemia. Journal of hematology & oncology 25 27071307
2008 Polycythemia vera transforming to acute myeloid leukemia and complex abnormalities including 9p homogeneously staining region with amplification of MLLT3, JMJD2C, JAK2, and SMARCA2. Cancer genetics and cytogenetics 25 18068534
2001 Targeted down-regulation of MLL-AF9 with antisense oligodeoxyribonucleotide reduces the expression of the HOXA7 and -A10 genes and induces apoptosis in a human leukemia cell line, THP-1. Leukemia 25 11681416
2018 Selective DOT1L, LSD1, and HDAC Class I Inhibitors Reduce HOXA9 Expression in MLL-AF9 Rearranged Leukemia Cells, But Dysregulate the Expression of Many Histone-Modifying Enzymes. Journal of proteome research 23 29972300
2018 Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9. EBioMedicine 21 30528456
2017 ZFP521 regulates murine hematopoietic stem cell function and facilitates MLL-AF9 leukemogenesis in mouse and human cells. Blood 21 28615219
2016 Modeling human MLL-AF9 translocated acute myeloid leukemia from single donors reveals RET as a potential therapeutic target. Leukemia 21 27780967
2012 An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model. Blood 20 22427200
2012 Spironolactone rescues Dot1a-Af9-mediated repression of endothelin-1 and improves kidney injury in streptozotocin-induced diabetic rats. PloS one 20 23077601
2015 Inactivation of Eed impedes MLL-AF9-mediated leukemogenesis through Cdkn2a-dependent and Cdkn2a-independent mechanisms in a murine model. Experimental hematology 19 26118502
2014 La-related protein 4B maintains murine MLL-AF9 leukemia stem cell self-renewal by regulating cell cycle progression. Experimental hematology 19 25534202
2021 Elucidating the Importance of DOT1L Recruitment in MLL-AF9 Leukemia and Hematopoiesis. Cancers 18 33562706
2016 Differential role of Id1 in MLL-AF9-driven leukemia based on cell of origin. Blood 18 26944543
2016 Smyd2 is a Myc-regulated gene critical for MLL-AF9 induced leukemogenesis. Oncotarget 18 27655694
2012 IGF signaling contributes to malignant transformation of hematopoietic progenitors by the MLL-AF9 oncoprotein. Experimental hematology 18 22613471
2012 An Af9 cis-element directly targets Dot1a to mediate transcriptional repression of the αENaC gene. American journal of physiology. Renal physiology 18 23152297
2023 AF9 sustains glycolysis in colorectal cancer via H3K9ac-mediated PCK2 and FBP1 transcription. Clinical and translational medicine 17 37565737
2020 The miR-5694/AF9/Snail Axis Provides Metastatic Advantages and a Therapeutic Target in Basal-like Breast Cancer. Molecular therapy : the journal of the American Society of Gene Therapy 17 33221433
2013 Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia. Blood 17 24021671
2012 Regulation of HOXA9 activity by predominant expression of DACH1 against C/EBPα and GATA-1 in myeloid leukemia with MLL-AF9. Biochemical and biophysical research communications 17 22902925
2009 The planar cell polarity (PCP) protein Diversin translocates to the nucleus to interact with the transcription factor AF9. Biochemical and biophysical research communications 17 19591803
2022 Design, Synthesis, and Biological Evaluations of DOT1L Peptide Mimetics Targeting the Protein-Protein Interactions between DOT1L and MLL-AF9/MLL-ENL. Journal of medicinal chemistry 15 35612819
2017 miR-564 inhibited metastasis and proliferation of prostate cancer by targeting MLLT3. European review for medical and pharmacological sciences 15 29164580
2021 Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced Leukemogenesis. Frontiers in oncology 14 34692539
2022 The bone marrow niche regulates redox and energy balance in MLL::AF9 leukemia stem cells. Leukemia 13 35618797
2020 High-fat diet intensifies MLL-AF9-induced acute myeloid leukemia through activation of the FLT3 signaling in mouse primitive hematopoietic cells. Scientific reports 13 32999332
2015 Phosphoinositide-dependent kinase 1 regulates leukemia stem cell maintenance in MLL-AF9-induced murine acute myeloid leukemia. Biochemical and biophysical research communications 13 25769952
2013 The elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors. PloS one 13 23762261
2012 MicroRNA-297b-5p/3p target Mllt3/Af9 to suppress lymphoma cell proliferation, migration and invasion in vitro and tumor growth in nude mice. Leukemia & lymphoma 13 22448917
2008 Expression of Leukaemia associated transcription factor Af9/Mllt3 in the cerebral cortex of the mouse. Gene expression patterns : GEP 13 19000783
2021 Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C. Oncogenesis 12 34789717
2019 Characterization of Copy Number Variations in Oral Cavity Squamous Cell Carcinoma Reveals a Novel Role for MLLT3 in Cell Invasiveness. The oncologist 12 31273053
2013 Rac1 signaling protects monocytic AML cells expressing the MLL-AF9 oncogene from caspase-mediated apoptotic death. Apoptosis : an international journal on programmed cell death 12 23624644
2012 Valproic acid triggers erythro/megakaryocyte lineage decision through induction of GFI1B and MLLT3 expression. Experimental hematology 12 22885124

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