Affinage

RUNX1T1

Protein CBFA2T1 · UniProt Q06455

Length
604 aa
Mass
67.6 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RUNX1T1 (ETO/MTG8) is a nuclear-matrix-associated transcriptional co-repressor that represses target genes by recruiting histone deacetylase complexes to DNA-bound transcription factors (PMID:8781439, PMID:12559562). It assembles with N-CoR/SMRT/Sin3A/HDAC corepressor machinery and serves as an obligate corepressor for sequence-specific factors including PLZF, Gfi-1/Gfi-1B, Bcl-6, and the RBP-Jκ/SHARP Notch complex, in each case enforcing HDAC-dependent silencing (PMID:12559562, PMID:12874834, PMID:14551142, PMID:18332109). High-affinity corepressor engagement depends on self-association through the NHR2 domain, which drives a dimer-to-tetramer transition required for SMRT/N-CoR binding and repression, while the MYND domain competes for the N-CoR binding site, the NHR3 domain binds PKA RIIα, and the eTAFH domain captures the AD1 motif of E proteins (E2A, HEB) (PMID:11113190, PMID:15333839, PMID:15231665, PMID:20430957). In physiology, RUNX1T1 is essential for gastrointestinal development, restrains intestinal stem cell genes (Lgr5, Ascl2) and ATOH1 enhancers downstream of Notch, and inhibits C/EBPβ during early adipogenesis (PMID:11463846, PMID:32553763, PMID:15509789); the family member MTGR1 mediates Prdm14-dependent repression in embryonic stem cells and germ-cell formation (PMID:26523391). The t(8;21) translocation fuses the RUNX1 runt domain to most of RUNX1T1, producing AML1-ETO, which acts as a dominant repressor of RUNX1 target genes and blocks fetal liver hematopoiesis in vivo (PMID:8334990, PMID:9054947). AML1-ETO requires CBFβ heterodimerization and NHR2-mediated oligomerization to block myeloid differentiation and enhance stem/progenitor self-renewal (PMID:19179469, PMID:20430957, PMID:11756147, PMID:12480707), silences CEBPA and E-protein function, redirects hematopoietic fate by suppressing scl, recruits DNMT1/DNMT3a to impose DNA hypermethylation, and is regulated by Lys43 methylation via EZH1, by TAF1 binding to acetylated Lys43, and by STUB1-mediated ubiquitin-degradation (PMID:11283671, PMID:15333839, PMID:18156164, PMID:15735013, PMID:25727291, PMID:31699991, PMID:31664040, PMID:28536267). It drives leukemic proliferation through AP-1/CCND2 and PLCG1 programs, and rapid degradation of AML1-ETO derepresses a core circuit that triggers RUNX1-dependent myeloid differentiation (PMID:30300583, PMID:34695195, PMID:33382982).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1993 High

    Defining the molecular lesion of t(8;21) AML by cloning the fusion gene established that a novel chromosome-8 gene, MTG8/ETO, is recurrently joined to AML1.

    Evidence RT-PCR, cDNA cloning, and Northern blot across t(8;21) patients and cell lines

    PMID:8334990 PMID:8353289

    Open questions at the time
    • Did not define the biochemical function of the fusion or wild-type ETO
    • No mechanism for how the fusion alters transcription
  2. 1996 Medium

    Characterizing endogenous ETO showed it is a nuclear-matrix phosphoprotein expressed in normal CD34+ progenitors, indicating a physiological role beyond the leukemic fusion.

    Evidence 32P-labeling immunoprecipitation, immunofluorescence, and subcellular fractionation in hematopoietic cells

    PMID:8781439

    Open questions at the time
    • Function of nuclear-matrix localization unresolved
    • No transcriptional targets identified
  3. 1997 High

    An AML1-ETO knock-in mouse demonstrated the fusion is a dominant inhibitor of normal AML1 function in vivo, phenocopying AML1/CBFβ loss.

    Evidence Gene-targeted knock-in mouse and fetal liver colony-forming assays

    PMID:9054947

    Open questions at the time
    • Embryonic lethality precluded analysis of leukemogenesis
    • Did not identify the repression mechanism
  4. 2001 High

    Identifying ETO as a corepressor and mapping NHR2-driven oligomerization established the core biochemical mechanism: self-association is required for high-affinity N-CoR/SMRT binding and for blocking differentiation.

    Evidence Co-IP, in vitro reconstitution, reporter repression, and differentiation assays with deletion/fusion mutants; parallel knockout and PKA-binding studies

    PMID:11113190 PMID:11463846 PMID:11593431 PMID:12480707 PMID:9447981

    Open questions at the time
    • Stoichiometry of the oligomer not yet resolved at this stage
    • Endogenous target genes not yet mapped
  5. 2003 High

    Cataloguing the corepressor partners (PLZF, Gfi-1/Gfi-1B, Bcl-6) and demonstrating ChIP occupancy at endogenous targets (c-FMS) established ETO as a general HDAC-recruiting corepressor for sequence-specific factors.

    Evidence Co-IP, immunofluorescence co-localization, ChIP, and HDAC-dependent reporter assays

    PMID:12559562 PMID:12773394 PMID:12874834 PMID:14551142

    Open questions at the time
    • Selectivity rules for partner recruitment unclear
    • Relative contribution of each partner to leukemia not weighted
  6. 2004 High

    Mapping the eTAFH–E-protein and MYND–N-CoR interfaces revealed how AML1-ETO silences E proteins and rewires corepressor competition, and showed the NHR3-NHR4 region restrains full leukemogenic potential.

    Evidence Co-IP, mass spectrometry, domain mapping, and in vivo leukemia models with truncation mutants

    PMID:15231665 PMID:15333839 PMID:15569932

    Open questions at the time
    • How the C-terminal restraint is relieved in patients unclear
    • Relative weighting of each interface for transformation not yet resolved
  7. 2005 High

    Linking RUNX1/MTG8 to DNMT1 recruitment at the IL-3 promoter connected the corepressor to heritable DNA methylation, broadening its silencing mechanism beyond histone deacetylation.

    Evidence ChIP on AML blasts, co-IP, and co-expression repression assays

    PMID:15735013

    Open questions at the time
    • Genome-wide extent of methylation targeting not defined here
    • Direct vs. indirect DNMT recruitment not distinguished
  8. 2008 High

    In vivo zebrafish, Notch-pathway, and domain-mapping studies showed AML1-ETO redirects hematopoietic fate by suppressing scl, disrupts ETO's normal RBP-Jκ/SHARP repression, and requires the RUNX1 DNA-binding and NHR2 domains for leukemia.

    Evidence Inducible transgenic zebrafish with scl rescue, co-IP/ChIP at Notch targets, and murine domain-deletion leukemia models

    PMID:18156164 PMID:18332109 PMID:19036704

    Open questions at the time
    • Mechanism of cofactor exchange at Notch targets not fully reconstituted
    • How fate redirection integrates with self-renewal unclear
  9. 2009 High

    Structure-guided dissection of individual interaction surfaces (eTAFH–HEB, CBFβ heterodimerization) parsed which contacts actually drive transformation, finding the E-protein contact dispensable but CBFβ binding essential.

    Evidence NMR structures, structure-guided mutagenesis, primary bone marrow clonogenic assays, and murine leukemia models

    PMID:19179469 PMID:19204326

    Open questions at the time
    • Why CBFβ is required despite the runt-fusion context not fully explained
    • Compensating activities of other domains not quantified
  10. 2010 High

    Biophysical and structural analysis resolved that NHR2 dimer-to-tetramer assembly, not the NHR3-PKA contact, is the obligate oligomerization step for DNA binding, gene regulation, and leukemia.

    Evidence Biophysical/energetic analysis, interface mutagenesis, DNA-binding and gene-expression assays, and murine transplantation; NMR of the NHR3-PKA RIIα complex with functional mutants

    PMID:20430957 PMID:20708017

    Open questions at the time
    • Druggability of the tetramer interface in vivo not established
    • How tetramerization templates target-gene selection unclear
  11. 2015 Medium

    Identifying the AML1/ETO–HIF1α loop driving DNMT3a expansion clarified how the fusion enforces tumor-suppressor hypermethylation as a maintainable circuit.

    Evidence Co-IP, ChIP, promoter reporters, siRNA knockdown, and xenograft models; structural/mechanistic work on MTGR1-Prdm14 in ESCs

    PMID:25727291 PMID:26523391

    Open questions at the time
    • Direct vs. cooperative DNMT3a transactivation not fully separated
    • Generality of the HIF1α circuit across patients untested
  12. 2019 High

    Discovery of EZH1-mediated Lys43 methylation and TAF1 binding to acetylated Lys43 established post-translational modification of the fusion as a tunable switch for its repressive activity and chromatin association.

    Evidence In vitro methylation assays, co-IP, ChIP/ChIP-seq, point mutagenesis, and self-renewal assays

    PMID:31664040 PMID:31699991

    Open questions at the time
    • Interplay between K43 methylation and acetylation not resolved
    • Upstream signals controlling these PTMs unknown
  13. 2020 High

    Defining the normal intestinal role and using rapid degron-based AML1-ETO removal connected the corepressor's physiological stem-cell restraint to its leukemic block, showing fusion loss triggers RUNX1-dependent differentiation.

    Evidence Mouse knockouts, organoids, CUT&RUN/ChIP-seq, and inducible degron with nascent transcript analysis

    PMID:32553763 PMID:33382982

    Open questions at the time
    • Direct primary targets of wild-type RUNX1T1 in hematopoiesis incompletely mapped
    • Kinetics of corepressor reassembly after differentiation unclear
  14. 2022 High

    Functional genomics nominated AP-1/CCND2 and PLCG1 as leukemia-specific effector programs of AML1-ETO, distinguishing oncogenic dependencies from normal HSPC requirements.

    Evidence ChIP-seq, RNAi/pharmacological inhibition, genetic inactivation in murine and human AML, and patient-derived xenografts; transcriptome-wide splicing analysis

    PMID:30300583 PMID:33483506 PMID:34695195

    Open questions at the time
    • How splicing regulation integrates with the transcriptional program unclear
    • Therapeutic window of these dependencies in patients untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RUNX1T1 oligomerization, partner selectivity, and the layered DNA/histone-methylation and PTM controls integrate to specify target-gene choice in normal versus leukemic cells remains unresolved.
  • No unified model linking tetramer assembly to genome-wide target specificity
  • Druggable interface or PTM node for clinical intervention not validated
  • Full physiological target set of wild-type RUNX1T1 across tissues incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3 GO:0042393 histone binding 2
Localization
GO:0005654 nucleoplasm 3 GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3
Partners
BCL6CBFBDNMT1EZH1MTGR1NCOR1RUNX1SMRT
Complex memberships
AML1-ETO fusion oligomer (t(8;21))N-CoR/SMRT-Sin3A-HDAC corepressor complexRBP-Jκ/SHARP Notch corepressor complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 The t(8;21) translocation juxtaposes AML1 (chromosome 21) with the novel gene MTG8 (chromosome 8), producing an AML1-MTG8 fusion transcript. The predicted fusion protein contains the runt homology region of AML1 and most of MTG8, which contains putative zinc finger DNA binding motifs and proline-rich regions. RT-PCR, cDNA cloning, Northern blot analysis The EMBO journal High 8334990
1993 AML1/MTG8(ETO) fusion junctions are constant in t(8;21) AML; MTG8 (ETO) transcripts (7.8 kb and 6.2 kb) are detected in t(8;21) cell lines but not in non-t(8;21) lines, confirming the fusion is a consistent feature of this translocation. RT-PCR, Northern blot analysis, cDNA cloning Blood High 8353289
1996 ETO protein is a nuclear phosphoprotein (phosphorylated on serine and threonine) and is associated with the nuclear matrix. ETO is coexpressed with AML1 in megakaryocytes and is unexpectedly present in normal CD34+ hematopoietic progenitor cells. Immunoprecipitation of 32P-labeled proteins, immunofluorescence, subcellular fractionation, Western blot Blood Medium 8781439
1997 Knock-in of AML1-ETO into the mouse AML1 locus causes embryonic lethality with hemorrhaging in the CNS and a severe block in fetal liver hematopoiesis, phenocopying homozygous loss of AML1 or CBFbeta, indicating AML1-ETO blocks normal AML1 function in vivo. Gene targeting (knock-in mouse model), hematopoietic colony forming unit assays Nature genetics High 9054947
1998 AML1-MTG8 fusion protein specifically and strongly interacts with MTGR1 (an MTG8 family member) through a 51-residue region (aa 488–538) containing NHR2. This interaction is required for AML1-MTG8 to stimulate G-CSF-dependent proliferation of myeloid progenitor cells and to interfere with AML1-dependent transcription. Co-immunoprecipitation, C-terminal deletion mutant analysis, ectopic expression in L-G myeloid progenitor cells Molecular and cellular biology High 9447981
1998 AML1/ETO(MTG8) accumulates CBFbeta (PEBP2beta) in the nucleus more efficiently than wild-type AML1, and associates with CBFbeta more effectively than wild-type AML1, dependent on the runt domain of the fusion protein. Immunofluorescence labeling, subcellular fractionation, co-immunoprecipitation in COS-7 cells Blood Medium 9473235
1998 ETO (MTG8) and AML1/ETO are associated with the nuclear matrix. A 40 amino acid region of ETO (aa 241–280), specifically lysine 265 and/or arginine 266, is sufficient for nuclear import via an importin-alpha/beta mediated pathway. ETO and AML1/ETO co-localize to punctate nuclear bodies distinct from PML bodies. GFP fusion fluorescence microscopy in living cells, mutational analysis, in vitro importin binding assay Oncogene Medium 10951564
2000 Atrophin-1 (DRPLA protein) interacts with ETO/MTG8 in the nuclear matrix. When co-transfected, atrophin-1 is recruited to nuclear structures containing mSin3A and histone deacetylases, and atrophin-1 represses transcription, suggesting ETO/MTG8 links atrophin-1 to nuclear receptor corepressor complexes. Yeast two-hybrid, co-transfection/co-localization in Neuro-2a cells, nuclear matrix fractionation from transgenic mouse brain, transcriptional repression assay The Journal of cell biology Medium 10973986
2001 ETO oligomerization mediated by NHR2 is required for interaction with corepressors SMRT and N-CoR. NHR2 mediates oligomerization of both ETO and AML1-ETO; polypeptides containing only NHR4 are insufficient for SMRT interaction, but fusion of NHR4 to a heterologous dimerization domain restores SMRT binding in vitro. NHR2 is also required for ETO repression function and inhibition of hematopoietic differentiation by AML1-ETO. Co-immunoprecipitation, in vitro binding assay, reporter gene repression assay, hematopoietic differentiation assay, deletion and fusion mutants Molecular and cellular biology High 11113190
2001 MTG8 interacts with the regulatory subunit of type II cAMP-dependent protein kinase (PKA RIIalpha) via its NHR3 domain (which contains a putative alpha-amphipathic helix characteristic of AKAPs). MTG8 and RIIalpha co-localize at the centrosome-Golgi area in lymphocytes. Co-immunoprecipitation, indirect immunofluorescence microscopy, domain mapping Oncogene Medium 11593431
2001 MTG8 knockout mice show severely reduced postnatal viability; approximately 25% lack a midgut and essentially all survivors show severe gut architecture disruption traceable to late embryonic development, establishing an essential physiological role for MTG8 in gastrointestinal development. Gene targeting (insertional inactivation), histology, developmental analysis Molecular and cellular biology High 11463846
2001 AML1-ETO suppresses C/EBPalpha expression, indirectly by inhibiting positive autoregulation of the CEBPA promoter. Conditional expression of AML1-ETO in U937 cells downregulates CEBPA mRNA, protein, and DNA-binding activity; conditional C/EBPalpha expression in Kasumi-1 cells restores neutrophilic differentiation. Conditional expression system, RT-PCR, Western blot, EMSA, neutrophilic differentiation assays Nature medicine High 11283671
2002 AML1-ETO expression in human CD34+ hematopoietic stem/progenitor cells inhibits colony formation by committed progenitors but enhances stem cell (CAFC) growth, resulting in a profound survival advantage and sustained CD34 expression over 5-week long-term cultures. Retroviral gene transfer into human CD34+ cells, clonogenic assays, long-term stromal cocultures, CAFC assay Blood High 11756147
2003 ETO associates with N-CoR/Sin3A/HDAC complexes in vivo and acts as a corepressor for the promyelocytic zinc finger protein (PLZF). ETO is localized to the nuclear matrix at sites coincident with HDAC enzymes and mSin3A, establishing ETO proteins as transcriptional corepressors. Co-immunoprecipitation, nuclear matrix fractionation, transcriptional reporter assays (reviewed) Gene Medium 12559562
2003 ETO interacts with Gfi-1 and Gfi-1B both in vitro and in vivo. Gfi-1 co-localizes with ETO in punctate subnuclear structures associated with the nuclear matrix, and Gfi-1 associates with HDAC-1, HDAC-2, and HDAC-3 when co-expressed in mammalian cells, suggesting ETO recruits Gfi-1 to HDAC complexes for transcriptional repression. In vitro binding assay, co-immunoprecipitation, immunofluorescence co-localization, nuclear matrix fractionation Journal of cellular biochemistry Medium 12874834
2003 AML1-ETO binds to the c-FMS intronic regulatory region (not just the promoter) in t(8;21) leukemic cells. AML1-ETO binding correlates with changes in histone modification patterns and increased association of histone deacetylases at the c-FMS locus, while not irreversibly displacing other transcription factors. In vivo footprinting, chromatin immunoprecipitation (ChIP) assay The EMBO journal High 12773394
2003 ETO acts as a bona fide corepressor for Bcl-6. ETO and Bcl-6 interact and co-localize in nuclear speckles in normal and malignant lymphoid tissue. ETO binds to the fourth zinc finger of Bcl-6, enhances Bcl-6 repression in an HDAC-dependent manner, and forms a complex with Bcl-6 on promoters of endogenous Bcl-6 target genes. Co-immunoprecipitation, immunofluorescence, reporter gene assay with HDAC inhibitor, chromatin immunoprecipitation Blood High 14551142
2004 AML1-ETO, as well as ETO alone, inhibits transcriptional activation by E proteins (E2A, HEB) through stable interactions mediated by a conserved ETO TAF4 homology domain (eTAFH) with a 17-amino acid motif (AD1) of E proteins, precluding recruitment of p300/CBP coactivators. In t(8;21) leukemic cells, AML1-ETO silences E protein function through an aberrant cofactor exchange mechanism. Co-immunoprecipitation, mass spectrometry, transcriptional reporter assays, domain mapping by mutagenesis Science High 15333839
2004 Deletion of the AML1-ETO C-terminal NCoR/SMRT-interacting domain (NHR3-NHR4 region) transforms AML1-ETO from an insufficient leukemogen into a potent leukemogenic protein that promotes in vitro growth and does not obstruct cell-cycle machinery, indicating this domain normally acts as a restraint on full leukemogenic activity. C-terminal truncation mutants, retroviral bone marrow transduction, murine transplantation model, cell cycle analysis Proceedings of the National Academy of Sciences of the United States of America High 15569932
2004 ETO/MTG8 is highly expressed in preadipocytes and acts as an inhibitor of C/EBPbeta during early adipogenesis. ETO prevents transcriptional activation of the C/EBPalpha promoter by C/EBPbeta and its accumulation in centromeric sites. ETO expression rapidly decreases upon initiation of adipogenesis; this decrease is essential for normal adipogenic gene expression. Expression analysis, gain/loss-of-function in preadipocyte differentiation assays, promoter reporter assays Molecular and cellular biology Medium 15509789
2005 RUNX1/MTG8 recruits DNMT1 to the IL-3 promoter, forming a RUNX1/MTG8-DNMT1 repressor complex. Physical association was confirmed by co-immunoprecipitation. Co-expression of RUNX1/MTG8 with DNMT1 enhances repression of IL-3, and both are concurrently released or stabilized at the promoter by HDAC or DNMT inhibitors respectively. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, co-transfection reporter assay in 293T cells Cancer research High 15735013
2001 siRNA-mediated suppression of AML1/MTG8 in Kasumi-1 and SKNO-1 t(8;21) leukemic cells increases susceptibility to TGFbeta1/vitamin D3-induced differentiation, upregulates CD11b, M-CSF receptor, and C/EBPalpha, induces cell shape changes, and reduces clonogenicity, demonstrating that AML1/MTG8 actively maintains a block to differentiation. siRNA knockdown, flow cytometry, colony formation assay, Western blot Blood High 12480707
2008 ETO (but not AML1/ETO) directly interacts with SHARP and augments SHARP-mediated repression of Notch target genes in an HDAC-dependent manner. ETO is a component of the endogenous RBP-Jkappa corepressor complex and is found at Notch target gene promoters. AML1/ETO overexpression or ETO knockdown each activates Notch target genes, indicating AML1/ETO disrupts ETO's normal repressive function at these genes. Co-immunoprecipitation, ChIP, reporter gene assay with HDAC inhibitor, siRNA knockdown, overexpression studies Molecular and cellular biology High 18332109
2008 AML1-ETO redirects myeloerythroid progenitors from erythroid to granulocytic fate in zebrafish by suppressing scl expression. Restoration of scl rescues AML1-ETO's effects on hematopoietic cell fate. HDAC inhibitor treatment restores scl and gata1 expression and ameliorates granulocytic accumulation. Inducible transgenic zebrafish model, genetic rescue (scl re-expression), pharmacological HDAC inhibition, in vivo imaging Development High 18156164
2009 The solution structure of the AML1-ETO eTAFH domain in complex with a HEB peptide was determined by NMR. Structure-guided mutations at key ETO residues for HEB binding do not impair AML1-ETO's ability to enhance clonogenic capacity of primary bone marrow cells or repress granulocyte differentiation, indicating the eTAFH–E protein interaction contributes relatively little to AML1-ETO activity. NMR structure determination, structure-guided mutagenesis, primary bone marrow clonogenic assay, differentiation assay Blood High 19204326
2009 CBFbeta is required for AML1-ETO activity: amino acid substitutions in the Runt domain disrupting CBFbeta heterodimerization (but not DNA binding) impair AML1-ETO's inhibition of granulocyte differentiation, abolish its enhancement of clonogenic potential of primary mouse bone marrow cells, and abrogate its cooperativity with TEL-PDGFbetaR in inducing AML in mice. Runt domain mutagenesis, primary mouse bone marrow clonogenic assay, murine leukemia transplantation model, differentiation assay Blood High 19179469
2010 The NHR2 domain of RUNX1/ETO mediates a dimer-to-tetramer transition. A cluster of 5 amino acids at the NHR2 dimer-tetramer interface are critical; substitutions abolish tetramer (but not dimer) formation. RUNX1/ETO dimers fail to bind DNA efficiently, fail to alter RUNX1-dependent gene expression, fail to block myeloid differentiation, fail to enhance hematopoietic progenitor self-renewal, and fail to induce leukemia in a murine transplantation model. Mutagenesis, biophysical analysis (structural/energetic), DNA binding assay, gene expression analysis, murine transplantation model, hematopoietic differentiation assay Blood High 20430957
2010 The solution structure of the AML1-ETO NHR3 domain in complex with PKA RIIalpha was determined by NMR. A key mutation abolishing PKA RIIalpha binding does not disrupt AML1-ETO's ability to enhance clonogenic capacity, repress proliferation or differentiation, or induce leukemia in vivo, indicating the NHR3-PKA RIIalpha interaction does not significantly contribute to AML1-ETO leukemogenesis. NMR structure determination, structure-guided mutagenesis, primary bone marrow clonogenic assay, in vivo leukemia model Journal of molecular biology High 20708017
2008 RUNX1/AML1 DNA-binding domain and the ETO NHR2-dimerization domain are critical for AML1-ETO9a-induced leukemia in mice; the NHR1 domain is not required. A region between NHR1 and NHR2 influences leukemia latency. Domain deletion/mutation mutants, murine bone marrow transduction and transplantation model, leukemia latency analysis Blood High 19036704
2015 AML1/ETO and HIF1alpha form a positive regulatory circuit and cooperate to transactivate the DNMT3a gene promoter, leading to DNA hypermethylation. Pharmacological or genetic disruption of the AML1/ETO-HIF1alpha loop causes DNA hypomethylation and re-expression of the hypermethylated tumor suppressor p15(INK4b). Co-immunoprecipitation, chromatin immunoprecipitation, promoter reporter assays, siRNA knockdown, xenograft mouse model Leukemia Medium 25727291
2017 The E3 ubiquitin ligase STUB1 binds to RUNX1 and RUNX1-RUNX1T1, induces their ubiquitination and proteasomal degradation, and promotes nuclear export of RUNX1. STUB1 overexpression shows substantial growth-inhibitory effect specifically in RUNX1-RUNX1T1-expressing myeloid leukemia cells. High-throughput binding assay, co-immunoprecipitation, ubiquitination assay, immunofluorescence, cell viability assay The Journal of biological chemistry Medium 28536267
2018 RUNX1/ETO cooperates with AP-1 to drive CCND2 (Cyclin D2) expression, maintaining leukemic cell cycle progression. Knockdown or pharmacological inhibition of CCND2 significantly impairs leukemic expansion and engraftment of patient-derived AML cells. RNAi screen guided by epigenomic profiling, ChIP-seq, siRNA knockdown, pharmacological inhibition, patient-derived xenograft model Cancer cell High 30300583
2019 TAF1 associates with K43-acetylated AML1-ETO. TAF1 binding sites significantly overlap with AML1-ETO binding sites genome-wide. TAF1 knockdown alters AML1-ETO chromatin association and expression of both activated and repressed AML1-ETO target genes. TAF1 is required for leukemic cell self-renewal, and its reduction promotes differentiation and apoptosis. Co-immunoprecipitation, ChIP-sequencing, siRNA knockdown, self-renewal assay Nature communications Medium 31664040
2019 EZH1 WD domain binds to the AML1-ETO NHR1 domain and methylates AML1-ETO at lysine 43 (Lys43) via its SET domain. This methylation augments AML1-ETO-dependent repression of tumor suppressor genes. Loss of Lys43 methylation by point mutation or domain deletion impairs AML1-ETO repressive activity. Co-immunoprecipitation, in vitro methylation assay, point mutation analysis, ChIP, reporter gene assay Nature communications High 31699991
2020 Rapid degradation of AML1-ETO using an inducible degron system, combined with CUT&RUN and nascent transcript analysis, identifies a small core transcriptional circuit directly regulated by AML1-ETO. Derepression of this network upon AML1-ETO removal is associated with RUNX1 DNA binding and triggers a transcription cascade leading to myeloid differentiation. Inducible protein degradation, CUT&RUN chromatin binding assay, nascent transcript analysis (TT-seq or equivalent) Molecular cell High 33382982
2020 MTG8 (RUNX1T1) and MTG16 are highly expressed in +4/5 early intestinal progenitors. Their expression is repressed by Notch signaling via ATOH1. Knockout of MTG8 or MTG16 in mice causes crypt hyperproliferation, expansion of intestinal stem cells, and impaired enterocyte differentiation. ChIP-seq shows MTG16 directly binds and represses promoters of intestinal stem cell genes (Lgr5, Ascl2) and ATOH1-regulated enhancers. Mouse knockout, intestinal organoids, ChIP-seq, RNA-seq, histology, immunohistochemistry Gastroenterology High 32553763
2021 RUNX1/RUNX1T1 regulates alternative RNA splicing in leukemic cells through two principal mechanisms: (i) regulation of alternative transcription start site selection affecting 5'-UTR structure, and (ii) control of splicing factor gene expression, generating alternative transcripts with new internal junctions. RNA-seq, transcriptome analysis, siRNA knockdown of RUNX1/RUNX1T1 Nature communications Medium 33483506
2022 PLCG1 is induced by AML1-ETO binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibits AML1-ETO-dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo, while PLCG1 is dispensable for normal hematopoietic stem and progenitor cell function. Proteomics, ChIP-seq (AE binding to PLCG1 locus), genetic inactivation (murine and human), in vivo leukemia model Blood High 34695195
2004 AML1-ETO decreases interactions between ETO-2/MTG16 and N-CoR. The MYND domain of AML1-ETO competitively occupies the ETO-2 binding site on N-CoR. Expression of the MYND domain alone in 32Dcl3 and human CD34+ cells prevents granulocyte but not macrophage differentiation, recapitulating a key effect of AML1-ETO. Co-immunoprecipitation, ectopic expression of MYND domain, hematopoietic differentiation assay Cancer research Medium 15231665
2015 The ETO-family co-repressor MTGR1 mediates Prdm14 repressive function in embryonic stem cells and primordial germ cell formation. MTGR1 tightly binds to the pre-SET/SET domains of Prdm14 and co-occupies its genomic targets. Crystal structure of the Prdm14-Mtgr1 complex was determined. Structure-guided point mutants and a monobody inhibitor of the Prdm14-Mtgr1 interaction abrogate Prdm14 function in mESC gene expression and PGC formation. Crystal structure determination, co-immunoprecipitation, ChIP-seq, structure-guided mutagenesis, synthetic monobody inhibitor, ESC differentiation assay eLife High 26523391

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. The EMBO journal 478 8334990
2001 AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nature medicine 394 11283671
1997 Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nature genetics 299 9054947
2005 AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. Proceedings of the National Academy of Sciences of the United States of America 246 15650049
1998 The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8(ETO) family. Blood 196 9596646
2002 The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells. Blood 183 11756147
2004 E protein silencing by the leukemogenic AML1-ETO fusion protein. Science (New York, N.Y.) 171 15333839
1993 Junctions of the AML1/MTG8(ETO) fusion are constant in t(8;21) acute myeloid leukemia detected by reverse transcription polymerase chain reaction. Blood 139 8353289
2002 AML1/MTG8 oncogene suppression by small interfering RNAs supports myeloid differentiation of t(8;21)-positive leukemic cells. Blood 138 12480707
1998 The AML1-MTG8 leukemic fusion protein forms a complex with a novel member of the MTG8(ETO/CDR) family, MTGR1. Molecular and cellular biology 135 9447981
2012 RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. Frontiers in bioscience (Landmark edition) 134 22201794
2003 The ETO (MTG8) gene family. Gene 134 12559562
2005 ETO-2 associates with SCL in erythroid cells and megakaryocytes and provides repressor functions in erythropoiesis. Molecular and cellular biology 122 16287841
2005 Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia. Cancer research 120 15735013
2001 Oligomerization of ETO is obligatory for corepressor interaction. Molecular and cellular biology 107 11113190
2008 AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression. Development (Cambridge, England) 103 18156164
2004 Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development. Proceedings of the National Academy of Sciences of the United States of America 103 15569932
2003 Gfi-1 attaches to the nuclear matrix, associates with ETO (MTG8) and histone deacetylase proteins, and represses transcription using a TSA-sensitive mechanism. Journal of cellular biochemistry 100 12874834
2000 Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription. The Journal of cell biology 96 10973986
2018 The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation. Cancer cell 92 30300583
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2004 Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice. Proceedings of the National Academy of Sciences of the United States of America 73 15477599
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2001 Gene targeting reveals a crucial role for MTG8 in the gut. Molecular and cellular biology 64 11463846
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2005 AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+ cells, allowing nerve growth factor-induced expansion. Proceedings of the National Academy of Sciences of the United States of America 59 15731354
2021 YTHDF2 is a potential target of AML1/ETO-HIF1α loop-mediated cell proliferation in t(8;21) AML. Oncogene 53 33958724
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2004 The oncogenic fusion protein RUNX1-CBFA2T1 supports proliferation and inhibits senescence in t(8;21)-positive leukaemic cells. BMC cancer 47 15298716
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2014 ETO family protein Mtg16 regulates the balance of dendritic cell subsets by repressing Id2. The Journal of experimental medicine 46 24980046
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2013 AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/β-catenin signaling pathway. Blood 45 23645839
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2021 RBM24 exacerbates bladder cancer progression by forming a Runx1t1/TCF4/miR-625-5p feedback loop. Experimental & molecular medicine 25 34021255
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2018 Characterization of RUNX1T1, an Adipogenesis Regulator in Ovine Preadipocyte Differentiation. International journal of molecular sciences 25 29701705
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2019 Gene mutation profile and risk stratification in AML1‑ETO‑positive acute myeloid leukemia based on next‑generation sequencing. Oncology reports 17 31638252
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