Affinage

MECOM

Histone-lysine N-methyltransferase MECOM · UniProt Q03112

Length
1230 aa
Mass
138.1 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 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

MECOM encodes multiple protein isoforms from a single locus whose opposing activities govern transcriptional programs in hematopoietic stem cells, vascular endothelium, and epithelial development, and which are co-opted in leukemia and solid tumors (PMID:9067573, PMID:21666053, PMID:37185814). The shorter EVI1 isoform is a zinc-finger transcriptional repressor: it binds the GACAAGATA/AGATA motif through its first zinc finger, a DNA-binding event essential for transforming activity (PMID:22039883), represses TGF-β signaling by physically engaging SMAD3 (PMID:11587364), and recruits CtBP and HDAC corepressors through a defined repression domain to silence target genes (PMID:11587364, PMID:11552981). EVI1 directly represses PTEN by recruiting polycomb repressive complexes, thereby activating AKT/mTOR signaling (PMID:21289308), and silences differentiation- and apoptosis-linked targets including MS4A3, RUNX1, and the miR-449a/miR-96 axis (PMID:25886616, PMID:28191887, PMID:21569010, PMID:23752186). In leukemic transformation EVI1 acts positively through direct activation of the ETS factor ERG via a conserved intragenic enhancer, with ERG re-expression bypassing EVI1 dependence (PMID:36095844), while its interaction with CTBP1/CTBP2 through a single PLDLS motif is indispensable for transformation and is a tractable therapeutic vulnerability (PMID:38748792). The longer PR-domain isoform MDS1-EVI1 (PRDM3) behaves antagonistically as a GATA-motif transcriptional activator (PMID:9067573) and is an H3K9me1-specific histone methyltransferase that, redundantly with PRDM16, maintains heterochromatin integrity and the nuclear lamina (PMID:22939622); through its PR-SET domain it engages the NuRD complex via RBBP4 in an isoform-specific manner (PMID:30462309). PRDM3 maintains hematopoietic stem cell quiescence and long-term repopulation via p57-Kip2/Cdkn1c (PMID:21666053) and is specifically required for MLL-AF9-driven leukemia through its methyltransferase activity (PMID:24021671). Beyond hematopoiesis, MECOM controls endothelial identity and angiogenesis through enhancer-mediated VEGF-pathway regulation (PMID:37185814), partners with PAX8 to drive adhesion/ECM programs in ovarian cancer (PMID:33903593), and with PRDM16 regulates NKX2-1-dependent alveolar epithelial differentiation (PMID:39284798).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1996 High

    Established that the MECOM locus produces both an independent EVI1 transcript and an MDS1/EVI1 fusion transcript, the latter adding an N-terminal PR domain—defining the structural basis for two functionally distinct isoforms.

    Evidence RT-PCR and intergenic splicing characterization in normal tissues

    PMID:8643684

    Open questions at the time
    • Did not define functional consequences of the PR domain
    • No enzymatic activity assigned to the PR domain at this stage
  2. 1997 High

    Demonstrated that the two isoforms are functionally opposed transcription factors—MDS1/EVI1 activates and EVI1 represses GATA-motif promoters—mapping the activating function to an acidic N-terminal segment.

    Evidence Luciferase reporter and Gal4-fusion assays with domain mapping

    PMID:9067573

    Open questions at the time
    • Corepressor identity for EVI1 repression not yet defined
    • In vivo relevance to hematopoiesis untested
  3. 1999 High

    Linked EVI1 to TGF-β signaling by showing physical SMAD3 interaction and demonstrating opposite isoform effects on growth inhibition, connecting the protein to a major antiproliferative pathway.

    Evidence Yeast two-hybrid plus 32Dcl3 cell functional assays

    PMID:10086725

    Open questions at the time
    • Domain mediating SMAD3 binding not yet mapped
    • Mechanism of transcriptional repression downstream of SMAD3 unresolved
  4. 2001 High

    Defined the repressive machinery of EVI1: SMAD3 binding via the first zinc finger plus CtBP and HDAC corepressor recruitment, explaining how EVI1 silences TGF-β and other targets.

    Evidence Co-immunoprecipitation, domain-deletion reporter assays, TSA inhibition (two studies)

    PMID:11552981 PMID:11587364

    Open questions at the time
    • Genome-wide target repertoire unknown
    • Relative contribution of CtBP vs HDAC not dissected
  5. 2002 High

    Showed the leukemic AML1/MDS1/EVI1 fusion uses both CtBP1-dependent and -independent repression and that CtBP1 binding is required for aberrant growth and differentiation of progenitors, tying corepressor recruitment to transformation.

    Evidence Reciprocal co-IP, domain-deletion reporter assays, 32Dcl3 and bone marrow functional assays

    PMID:12082639

    Open questions at the time
    • CtBP1-independent repression mechanism not defined
    • Direct target genes of the fusion not yet identified
  6. 2004 High

    Identified a translational-control axis whereby the AME fusion activates calreticulin to suppress CEBPA protein, revealing post-transcriptional disruption of a myeloid differentiation factor.

    Evidence Conditional expression, EMSA, siRNA rescue of CRT

    PMID:15326310

    Open questions at the time
    • Whether full EVI1 (non-fusion) uses the same axis untested
    • Direct vs indirect activation of CRT not fully resolved
  7. 2007 Medium

    Mapped the 8th zinc finger as an oligomerization domain that binds RUNX1 and disrupts its DNA binding, identifying a mechanism by which EVI1 antagonizes a master myeloid regulator.

    Evidence In vitro binding, reporter assays, 32Dcl3 differentiation block

    PMID:17575132

    Open questions at the time
    • Single lab; reciprocal in vivo validation limited
    • Endogenous chromatin context of RUNX1 antagonism untested
  8. 2011 High

    Established direct PTEN repression by EVI1 through polycomb recruitment, providing a mechanistic route to AKT/mTOR activation in leukemia and a rapamycin-sensitive vulnerability.

    Evidence ChIP, co-IP, murine BMT model, rapamycin sensitivity, human sample validation

    PMID:21289308

    Open questions at the time
    • Which polycomb subunits are directly bound not fully defined
    • Generality across MECOM-rearranged subtypes not exhaustive
  9. 2011 High

    Defined a non-coding regulatory axis (EVI1 represses miR-449a, derepressing NOTCH1/BCL2) and structurally validated that ZF1 binding to GACAAGATA is essential for transformation, connecting DNA binding to oncogenic output.

    Evidence ChIP, miRNA profiling and re-expression rescue; DNase footprinting, EMSA, polyamide inhibition, colony assays

    PMID:21569010 PMID:22039883

    Open questions at the time
    • miR-449a axis from single lab (Medium)
    • Specificity of polyamide inhibition in vivo not established
  10. 2011 High

    Demonstrated that the PR-domain isoform Mds1-Evi1 is HSC-restricted and essential for stem cell quiescence and long-term repopulation via p57-Kip2/Cdkn1c, distinguishing its physiological role from EVI1.

    Evidence lacZ knock-in mouse, BMT, RNA-seq, retroviral rescue

    PMID:21666053

    Open questions at the time
    • Whether methyltransferase activity is required for HSC function untested here
    • Direct vs indirect regulation of Cdkn1c not resolved
  11. 2012 High

    Identified PRDM3/PRDM16 as redundant H3K9me1-specific methyltransferases required to seed heterochromatin formation and maintain the nuclear lamina, assigning a catalytic chromatin function to the PR domain.

    Evidence In vitro methyltransferase assay, MEF analyses, DNA-FISH, EM, siRNA

    PMID:22939622

    Open questions at the time
    • Genomic loci directed by PRDM3 specifically vs PRDM16 not resolved
    • Link between this catalytic role and leukemia not addressed here
  12. 2012 Medium

    Showed EVI1 activation produces biphasic growth effects and a stemness/anti-proliferative transcriptional signature, illustrating dose- and time-dependent control of progenitor fate.

    Evidence Inducible lentiviral expression, microarray, cell cycle analysis

    PMID:23212151

    Open questions at the time
    • Single lab; direct vs indirect targets not separated
    • In vivo relevance of biphasic effect untested
  13. 2013 High

    Extended MECOM function to non-hematopoietic contexts: KRAS upregulation via miR-96 in pancreatic cancer, distal tubule/nephron patterning upstream of Notch in zebrafish, and PR-domain dependence of MLL-AF9 leukemia.

    Evidence shRNA knockdown and miRNA validation; morpholino knockdown with NICD rescue; ME-deficient mouse transformation panel with PR-domain mutants

    PMID:23752186 PMID:24021671 PMID:24309209

    Open questions at the time
    • Mechanism of miR-96 regulation (direct vs indirect) not defined
    • Why PR domain is selectively required for MLL fusions but not others unexplained
  14. 2015 Medium

    Identified MS4A3 as a directly repressed pro-apoptotic EVI1 target whose re-expression counteracts EVI1-driven tumor growth, adding to the repressed differentiation/apoptosis program.

    Evidence Reporter assay, ChIP, qRT-PCR, xenograft rescue

    PMID:25886616

    Open questions at the time
    • Single lab
    • Contribution relative to other EVI1 targets unquantified
  15. 2017 High

    Connected EVI1 transcriptional repression of RUNX1 to a metabolic dependency (CKMT1-dependent arginine-creatine ATP buffering), revealing a druggable metabolic vulnerability in EVI1+ AML.

    Evidence shRNA screen, transcriptomics/metabolomics, cyclocreatine, xenograft and primary AML models, metabolic rescue

    PMID:28191887

    Open questions at the time
    • Whether CKMT1 dependency extends to all MECOM rearrangements untested
    • Direct chromatin binding at CKMT1 not shown
  16. 2017 Medium

    Demonstrated isoform-specific autoregulation of the MECOM locus, with EVI1-145kDa autoactivating and MDS1-EVI1 repressing EVI1 transcription, and opposing effects on HSPC maintenance.

    Evidence EVI1-promoter luciferase reporters, retroviral isoform expression, colony assays

    PMID:28391050

    Open questions at the time
    • Single lab
    • Endogenous autoregulatory loop not validated genetically
  17. 2019 Medium

    Revealed that distinct fusion contexts (RUNX1-EVI1 vs RUNX1-ETO) impose different chromatin and transcriptional programs, and that EVI1 drives OXPHOS/glutamine metabolic reprogramming sensitizing cells to L-asparaginase.

    Evidence ChIP-seq/ATAC-seq/RNA-seq dependency assays; extracellular flux, metabolomics, in vivo L-asparaginase

    PMID:28538183 PMID:31649131

    Open questions at the time
    • Both single-lab studies
    • Mechanistic link between EVI1 transcription factor activity and metabolic shift incomplete
  18. 2019 High

    Defined the isoform-specific PRDM3-NuRD interaction at atomic resolution, showing RBBP4 binds the PR-SET N-terminal residues in the histone H3-binding groove, distinguishing PRDM3's chromatin partnerships from EVI1.

    Evidence Proteomics, ITC (Kd 3.0 µM), X-ray crystallography of PRDM3 peptide/RBBP4

    PMID:30462309

    Open questions at the time
    • Functional consequence of NuRD recruitment on target genes not defined here
    • Whether RBBP4 binding competes with H3 substrate engagement in vivo unresolved
  19. 2021 High

    Extended MECOM to epithelial/solid-tumor and stress contexts: PRDM3-PAX8 complex driving adhesion/ECM programs in ovarian cancer and SOX9-driven MECOM enabling acinar dedifferentiation and survival via ERK.

    Evidence Co-IP, ChIP-seq, xenografts; lineage tracing, mouse loss-of-function, SOX9 regulation, ERK analysis

    PMID:33762742 PMID:33903593

    Open questions at the time
    • PAX8 study single-lab co-IP for complex assembly
    • Direct MECOM target genes in acinar dedifferentiation not enumerated
  20. 2022 High

    Showed that mutant SF3B1 generates a novel in-frame EVI1 splice isoform via cryptic splice-site usage that enhances HSC self-renewal and accelerates leukemogenesis, linking spliceosome mutation to EVI1 oncogenicity.

    Evidence RNA splicing analysis, humanized inv(3)/Sf3b1 mouse model, HSC self-renewal assays

    PMID:35709354

    Open questions at the time
    • Biochemical mechanism by which the 6-aa insertion enhances function unknown
    • Frequency of this isoform across patients not addressed
  21. 2023 High

    Established direct enhancer-driven activation as a core EVI1 oncogenic mechanism—ERG via an intragenic enhancer in AML and ETS2 via a disease-specific super-enhancer in colorectal/IBD—positioning EVI1 as a transcriptional activator at long-range regulatory elements.

    Evidence CRISPR screens, ChIP-seq, RNA-seq, EVI1-withdrawal and ERG epistasis; ChIP-seq, Hi-C, reporter and knockdown assays

    PMID:36095844 PMID:36609474

    Open questions at the time
    • ETS2 study single-lab (Medium)
    • How activation vs repression is determined at different loci not mechanistically explained
  22. 2023 High

    Defined a developmental requirement for MECOM in endothelial identity and angiogenesis through enhancer chromatin loops regulating VEGF-pathway genes, broadening its physiological role beyond hematopoiesis.

    Evidence siRNA knockdown, scRNA-seq, Hi-C, DNase-seq, ChIP-seq, zebrafish angiogenesis

    PMID:37185814

    Open questions at the time
    • Isoform responsible (EVI1 vs MDS1-EVI1) in endothelium not dissected
    • Direct VEGF-pathway target genes vs indirect effects not fully separated
  23. 2024 High

    Pinpointed a single PLDLS motif mediating EVI1-CTBP1/CTBP2 interaction as indispensable for leukemic transformation and showed a decoy peptide inhibits MECOM-rearranged AML, validating the corepressor interface as a therapeutic target; PRDM3/PRDM16 were also shown jointly required for NKX2-1-dependent alveolar differentiation.

    Evidence Proteomics, co-IP, PLDLS-decoy competition, xenotransplant; conditional lung knockouts with scRNA-seq, ATAC-seq, CUT&RUN

    PMID:38748792 PMID:39284798

    Open questions at the time
    • In vivo pharmacology of decoy peptide beyond xenografts untested
    • Mechanism by which PRDM3/16 set chromatin accessibility at NKX2-1 targets not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single locus's opposing repressor (EVI1) and activator/methyltransferase (MDS1-EVI1/PRDM3) isoforms are deployed context-specifically—and what governs the switch between long-range enhancer activation and corepressor-mediated silencing at individual loci—remains unresolved.
  • No unified model linking PR-domain catalytic activity to isoform-specific gene programs in vivo
  • Determinants of activation vs repression at a given target not defined
  • Therapeutic selectivity of targeting EVI1 over PRDM3 isoform unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 2 GO:0042393 histone binding 2 GO:0016740 transferase activity 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CTBP1CTBP2HDAC1PAX8RBBP4RUNX1SMAD3
Complex memberships
CtBP/HDAC corepressor complexNuRD complexpolycomb repressive complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 MDS1 exists as both an independent transcript and as a fusion transcript with EVI1 (MDS1/EVI1) in normal tissues, producing a protein with ~40% amino acid homology to the PR domain of the RIZ retinoblastoma-interacting zinc-finger protein at the N-terminus of EVI1. RT-PCR, sequence analysis, intergenic splicing characterization Proceedings of the National Academy of Sciences of the United States of America High 8643684
1997 MDS1/EVI1 is a strong transcriptional activator of promoters containing the AGATA (GATA-binding) motif, whereas EVI1 (the shorter isoform lacking the PR/MDS1 N-terminus) is a transcriptional repressor; EVI1 represses GATA-1-driven activation while MDS1/EVI1 does not; the activating function of MDS1/EVI1 maps to an acidic segment encoded by exons 2–3 in the 5' region. Reporter gene (luciferase) assays, Gal4 DNA-binding domain fusion constructs, comparative expression analysis Leukemia High 9067573
1999 EVI1 physically interacts with SMAD3 (an intracellular TGF-β signaling mediator) via a yeast two-hybrid assay; MDS1/EVI1 enhances TGF-β1-mediated growth inhibition whereas the leukemic fusion AML1/MDS1/EVI1 abrogates it; MDS1/EVI1 has no effect on G-CSF-induced granulocytic differentiation but AML1/MDS1/EVI1 blocks differentiation. Yeast two-hybrid, cell-line functional assays (32Dcl3), reporter gene assays Leukemia High 10086725
2001 EVI1 represses TGF-β signaling by physically interacting with SMAD3 through its first zinc-finger domain, suppressing SMAD3 transcriptional activity; EVI1 also recruits CtBP as a corepressor through a CtBP-binding motif (amino acids 544–607), and histone deacetylase (HDAC) inhibitor TSA alleviates EVI1-mediated TGF-β repression. Co-immunoprecipitation, reporter gene assays, domain-deletion analysis, pharmacological HDAC inhibition Cancer chemotherapy and pharmacology High 11587364
2001 Both EVI1 and MDS1/EVI1 repress transcription from reporter constructs containing EVI1 binding sites and both physically interact with histone deacetylase (HDAC) in mammalian cells; this interaction can be recapitulated in vitro and is mediated by a previously characterized repression domain whose activity is alleviated by TSA. Reporter gene assays, co-immunoprecipitation (in vivo and in vitro), HDAC inhibitor (TSA) British journal of haematology Medium 11552981
2002 The leukemic fusion protein AML1/MDS1/EVI1 (AME) physically interacts in vivo with CtBP1 and HDAC1 through distinct regions of AME; AME represses gene transcription by both CtBP1-dependent and CtBP1-independent mechanisms; the AME–CtBP1 interaction is required for growth upregulation and abnormal differentiation of murine hematopoietic precursor 32Dcl3 cells and bone marrow progenitors. Co-immunoprecipitation, reporter gene assays, domain-deletion analysis, cell functional assays Oncogene High 12082639
2004 The leukemic fusion protein AML1/MDS1/EVI1 (AME) suppresses CEBPA protein and DNA-binding activity (~90%) without changing CEBPA mRNA levels; AME strongly activates calreticulin (CRT), which inhibits CEBPA translation; siRNA knockdown of CRT restores CEBPA protein levels in AME-expressing cells. Conditional expression system, western blot, EMSA, siRNA knockdown, quantitative RT-PCR Proceedings of the National Academy of Sciences of the United States of America High 15326310
2007 EVI1 represses RUNX1 (AML1) function: the 8th zinc finger motif of EVI1/MDS1/EVI1 is an oligomerization domain that interacts with RUNX1 in vitro, altering RUNX1's DNA-binding ability and reporter gene regulation; in vivo, expression of the isolated 8th zinc finger motif of EVI1 blocks G-CSF-induced granulocytic differentiation of 32Dcl3 cells, leading to cell death. In vitro binding assay, reporter gene assay, cell functional assay (32Dcl3 differentiation model) Cancer research Medium 17575132
2011 EVI1 directly represses PTEN transcription in murine bone marrow, leading to activation of AKT/mTOR signaling; EVI1 binds to polycomb group proteins and recruits polycomb repressive complexes to the PTEN locus for its down-regulation; this mechanism is recapitulated in human leukemic cells. ChIP assay, co-immunoprecipitation, murine bone marrow transplantation model, rapamycin sensitivity assay, human patient sample validation Blood High 21289308
2011 PR-domain-containing Mds1-Evi1 (ME) is exclusively expressed in hematopoietic stem cells (HSCs); ME deficiency reduces HSC number and completely eliminates long-term repopulation capacity while shifting the stem cell compartment from quiescence to active cycling; ME preferentially rescues long-term HSC defects relative to EVI1; ME regulates p57-Kip2 (Cdkn1c) expression and reintroduction of ME normalizes p57-Kip2 expression and growth control. lacZ knock-in mouse model, bone marrow transplantation, RNA-seq in Lin-Sca-1+c-Kit+ cells, retroviral reintroduction rescue experiments Blood High 21666053
2012 Prdm3 (MECOM/MDS1-EVI1) and Prdm16 act as redundant H3K9me1-specific histone methyltransferases (KMTs) that direct cytoplasmic H3K9me1 methylation; simultaneous depletion of Prdm3 and Prdm16 abolishes H3K9me1 methylation, prevents Suv39h-dependent H3K9me3 trimethylation, derepresses major satellite transcription, and causes disintegration of heterochromatic foci and disruption of the nuclear lamina. Biochemical in vitro methyltransferase assay, in vivo mouse embryonic fibroblast analyses, DNA-FISH, electron microscopy, siRNA depletion Cell High 22939622
2012 EVI1 activation in hematopoietic progenitor cells causes biphasic effects: initial growth inhibition with retarded myeloid differentiation and dose-dependent G0/G1 cell cycle arrest; EVI1 upregulates stemness genes (Aldh1a1, Abca1, Cdkn1b, Cdkn1c) and downregulates genes for DNA replication (cyclins) and DNA repair (Brca1, Brca2, Rad51) within 24 hours. Inducible lentiviral expression, gene expression microarray, cell cycle analysis Leukemia Medium 23212151
2013 EVI1 upregulates KRAS expression in pancreatic cancer cells by suppressing miR-96, a potent KRAS suppressor; EVI1 depletion causes inhibition of cell growth and migration. shRNA knockdown, miRNA target validation, cell proliferation/migration assays Oncogene Medium 23752186
2013 In zebrafish, mecom is necessary for distal tubule formation and restricts proximal tubule formation and multiciliated cell (MCC) fate choice during nephron development; mecom acts upstream of Notch signaling to promote it (ectopic NICD rescues MCC expansion in mecom morphants); retinoic acid (RA) and mecom have opposing roles in proximal-distal segment patterning, with RA inhibiting mecom. Morpholino knockdown, genetic epistasis (DAPT/γ-secretase inhibitor, NICD overexpression rescue), zebrafish developmental phenotype analysis Developmental biology High 24309209
2013 The PR domain of MDS1-EVI1 (ME isoform) is essential for MLL-AF9-induced leukemic transformation in vitro and in vivo; ME is specifically required for MLL-AF9 and MLL-ENL leukemia but not for Nup98-HOXA9, MEIS1-HOXA9, or E2A-Hlf transformation; the PR domain histone methyltransferase activity is required for this function. ME-deficient mouse model, in vitro transformation assays, bone marrow transplantation, retroviral transduction with PR-domain mutants Blood High 24021671
2011 EVI1 directly represses MIR449A via promoter occupation; MIR449A targets NOTCH1 and BCL2; the EVI1-MIR449A-NOTCH1/BCL2 regulatory axis contributes to survival of MECOM-rearranged leukemic cells. ChIP (chromatin immunoprecipitation), miRNA expression profiling, knockdown/re-expression models, apoptosis assays British journal of haematology Medium 21569010
2011 Targeting EVI1's first zinc finger domain (ZF1) DNA-binding site with a synthetic pyrrole-imidazole polyamide blocks EVI1 binding to the GACAAGATA motif; structure-function studies showed that ZF1-mediated DNA binding to GACAAGATA is essential for EVI1 transforming activity. DNase I footprinting, EMSA, in vivo CAT reporter assay, colony formation assay, structure-function mutagenesis Biochemistry High 22039883
2015 EVI1 directly represses MS4A3 transcription by binding to a proximal promoter region; experimental re-expression of MS4A3 in EVI1-overexpressing cells counteracts EVI1-promoted tumor growth by increasing apoptosis in a xenograft model. Reporter gene assay (luciferase), ChIP, qRT-PCR, xenograft tumor model Journal of hematology & oncology Medium 25886616
2017 EVI1 overexpression promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1; CKMT1-dependent arginine-creatine metabolism (ATP buffering via mitochondrial creatine kinase) is required for survival of EVI1-positive AML cells; CKMT1 inhibition alters mitochondrial respiration and ATP production, and phosphocreatine reactivation of the arginine-creatine pathway abrogates these effects. shRNA screen, transcriptomic and metabolomic profiling, CKMT1 shRNA knockdown, small molecule (cyclocreatine) treatment, xenograft models, primary AML mouse models, metabolic flux analysis Nature medicine High 28191887
2017 RUNX1-EVI1 (from t(3;21)) directs a stem cell-like transcriptional network reliant on GATA2 and displays distinct chromatin binding patterns and gene expression programs compared to RUNX1-ETO despite sharing the same RUNX1 DNA-binding domain; both AML types are dependent on continuous expression of their respective fusion proteins. ChIP-seq, ATAC-seq, RNA-seq, transcription factor dependency assays Cell reports Medium 28538183
2019 PRDM3 (MDS1-EVI1) directly interacts with the NuRD chromatin remodeling complex specifically through its N-terminal PR-SET domain residues, primarily via RBBP4; this interaction is isoform-specific (absent in EVI1/ΔPR isoform); RBBP4 binds to N-terminal amino acid residues of PRDM3 within the conserved histone H3-binding groove, as determined by X-ray crystal structures. Proteomics (interactome comparison of full-length vs. ΔPR isoforms), isothermal titration calorimetry (Kd = 3.0 μM), X-ray crystallography of PRDM3 N-terminal peptide/RBBP4 complex Nucleic acids research High 30462309
2021 MECOM (MDS1-EVI1/PRDM3) forms a protein complex with the transcription factor PAX8; PRDM3 interaction with PAX8 was mapped in vitro and in vivo; together PAX8 and PRDM3 regulate a specific gene expression module involved in adhesion and extracellular matrix at a subset of PAX8 genomic binding sites; the MECOM locus and PAX8 sustain in vivo tumor growth in ovarian cancer. Co-immunoprecipitation, in vitro and in vivo interaction mapping, ChIP-seq, transcriptomics, xenograft in vivo tumor model Nature communications High 33903593
2021 MECOM depletion impairs human endothelial cell differentiation and function and zebrafish angiogenesis; MECOM binds enhancers that form chromatin loops to regulate endothelial cell identity genes; the VEGF signaling pathway is a key transcriptional target of MECOM in endothelial cells. MECOM siRNA knockdown, single-cell RNA-seq, Hi-C, DNase-seq, ChIP-seq, RNA-seq, zebrafish angiogenesis assay Nature communications High 37185814
2022 Oncogenic SF3B1 mutations generate a novel in-frame EVI1 splice isoform containing a 6-amino acid insertion at the 3' end of the second zinc finger domain; this isoform enhances hematopoietic stem cell self-renewal and accelerates leukemogenesis in vivo; the mutant SF3B1 spliceosome uses an exonic splicing enhancer within EVI1 exon 13 to drive usage of a cryptic branch point and aberrant 3' splice site within intron 12. RNA splicing analysis, in vivo mouse leukemogenesis model (humanized inv(3) allele + mutant Sf3b1), HSC self-renewal assays, molecular characterization of splice site usage Blood High 35709354
2023 EVI1 drives leukemogenesis primarily through direct transcriptional activation of the ETS transcription factor ERG; EVI1 occupies a conserved intragenic enhancer region of ERG in AML cell lines and primary AML; suppression of ERG induces terminal differentiation of EVI1-driven AML cells, whereas ectopic ERG expression abrogates dependence on EVI1. CRISPR genome-wide screens, ChIP-seq, RNA-seq, inducible EVI1 withdrawal models, ERG knockdown/overexpression epistasis in vitro and in vivo Blood High 36095844
2024 EVI1 interaction with CTBP1 and CTBP2 via a single PLDLS motif is indispensable for leukemic transformation; a 4× PLDLS repeat decoy construct outcompetes EVI1 binding to CTBP1/CTBP2 and inhibits proliferation of 3q26/MECOM-rearranged AML in vitro and in xenotransplant models. Protein folding predictions, proteomics, co-immunoprecipitation, PLDLS-decoy peptide competition assay, in vitro proliferation assay, xenotransplant mouse model Science advances High 38748792
2006 Arsenic trioxide (ATO) degrades the AML1/MDS1/EVI1 (AME) fusion protein via the ubiquitin-proteasome pathway (for EVI1 moiety) and in a proteasome-independent manner (for MDS1 moiety); ATO treatment induces differentiation and apoptosis in AME leukemic cells in vitro and reduces tumor load in vivo. Western blot protein degradation assay, proteasome inhibitor experiments, cell differentiation/apoptosis assays, mouse transplant model Cancer research Medium 17145882
2024 Combined deletion of Prdm3 and Prdm16 in lung endoderm causes perinatal lethality due to respiratory failure with loss of AT2 cells and accumulation of partially differentiated AT1 cells; PRDM3 and PRDM16 regulate chromatin accessibility at NKX2-1 transcriptional targets critical for AT2 cell differentiation; lineage-specific deletion in AT2 cells causes lineage infidelity with partial AT1 fate acquisition. Conditional knockout mouse models (single-cell RNA-seq, bulk ATAC-seq, CUT&RUN), lung morphological and functional phenotyping Nature communications High 39284798
2017 EVI1 isoforms (EVI1-145kDa, EVI1-Δ324, MDS1-EVI1) regulate EVI1's own transcription through distinct promoter regions: EVI1-145kDa activates EVI1 transcription (autoactivation), whereas EVI1-Δ324 and MDS1-EVI1 act as repressors of EVI1 transcription; EVI1-145kDa prolongs maintenance of hematopoietic stem and progenitor cells while MDS1-EVI1 represses colony replating capacity. Reporter gene assays (luciferase with EVI1 promoter regions), retroviral expression of isoforms, hematopoietic colony assays Biochimica et biophysica acta. Gene regulatory mechanisms Medium 28391050
2013 EVI1 splice variants in ovarian cancer (including Del190-515) bind CtBP1 and SMAD3 similar to wild-type EVI1, but localize preferentially to PML nuclear bodies; EVI1 wild-type and EVI1(Del427-515) (but not Del190-515) increase cyclin E1 LMW expression and promote cell cycle progression; knockdown of MDS1/EVI1 and EVI1(Del190-515) increases claudin-1 expression with reduction in cell migration. Co-immunoprecipitation, immunofluorescence localization, cell cycle analysis, western blot, knockdown experiments Molecular oncology Medium 23517670
2021 MECOM (EVI1) expression in acinar cells during dedifferentiation is directly regulated by SOX9; MECOM deficiency in acinar cells impairs cell adhesion, increases acinar cell death, suppresses dedifferentiation, and limits ERK signaling; MECOM permits acinar cell survival under stress by enabling cellular dedifferentiation. Lineage tracing, RNA sequencing, genetic loss-of-function (mouse), SOX9 correlation and direct regulation assay, ERK pathway analysis Cell death and differentiation Medium 33762742
2019 EVI1 overexpression in AML cells triggers metabolic reprogramming including acceleration of oxidative phosphorylation (OXPHOS) prior to glycolysis activation, with increased dependency on glutamine as an energy source; EVI1 drives production of TCA cycle metabolites; low ASNS expression in EVI1+ cells confers sensitivity to L-asparaginase. Extracellular flux analysis (XFp), mouse AML models (MLL-AF9/Evi1), metabolomics, cell viability assays, in vivo L-asparaginase treatment Haematologica Medium 31649131
2023 EVI1 activates the ETS2 super-enhancer in colorectal cancer/IBD through binding to a disease-specific super-enhancer that physically contacts the ETS2 promoter; an IBD-risk SNP in the ETS2 super-enhancer modulates ETS2 expression by affecting MECOM binding; silencing MECOM significantly downregulates ETS2 in CRC cells. ChIP-seq, Hi-C, enhancer RNA analysis, reporter gene assays, MECOM knockdown, cell colony-formation and migration assays Cell death & disease Medium 36609474

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nature medicine 925 16582916
2012 Prdm3 and Prdm16 are H3K9me1 methyltransferases required for mammalian heterochromatin integrity. Cell 262 22939622
2008 High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood 227 18272813
1996 Intergenic splicing of MDS1 and EVI1 occurs in normal tissues as well as in myeloid leukemia and produces a new member of the PR domain family. Proceedings of the National Academy of Sciences of the United States of America 189 8643684
2004 EVI1 induces myelodysplastic syndrome in mice. The Journal of clinical investigation 159 15343390
2015 Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. Nature communications 146 25849990
2000 A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood 140 11050005
1994 Expression of EVI1 in myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations. Blood 136 8049440
2005 Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells. Blood 134 15933056
2007 Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis. Blood 132 17227832
2007 The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Gene 127 17507183
2011 Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins. Blood 126 21289308
1997 Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders. Cancer research 125 9044825
1997 The EVI1 gene in myeloid leukemia. Leukemia 109 9447815
1999 MDS1/EVI1 enhances TGF-beta1 signaling and strengthens its growth-inhibitory effect but the leukemia-associated fusion protein AML1/MDS1/EVI1, product of the t(3;21), abrogates growth-inhibition in response to TGF-beta1. Leukemia 100 10086725
2017 The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia. Nature medicine 93 28191887
1997 The leukemia-associated gene MDS1/EVI1 is a new type of GATA-binding transactivator. Leukemia 89 9067573
2011 PR-domain-containing Mds1-Evi1 is critical for long-term hematopoietic stem cell function. Blood 87 21666053
2005 EVI1 and hematopoietic disorders: history and perspectives. Gene 82 16314052
2013 Zebrafish nephrogenesis is regulated by interactions between retinoic acid, mecom, and Notch signaling. Developmental biology 80 24309209
2018 MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. Blood advances 79 29540340
2004 The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin. Proceedings of the National Academy of Sciences of the United States of America 75 15326310
2012 EVI1 is critical for the pathogenesis of a subset of MLL-AF9-rearranged AMLs. Blood 71 22553314
2000 Human AML1/MDS1/EVI1 fusion protein induces an acute myelogenous leukemia (AML) in mice: a model for human AML. Proceedings of the National Academy of Sciences of the United States of America 71 10677531
2014 EVI1-rearranged acute myeloid leukemias are characterized by distinct molecular alterations. Blood 68 25331116
2012 Activation of Evi1 inhibits cell cycle progression and differentiation of hematopoietic progenitor cells. Leukemia 67 23212151
2023 Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet. Haematology 62 38065203
2001 Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia. Oncogene 62 11781838
2016 Review: Aberrant EVI1 expression in acute myeloid leukaemia. British journal of haematology 61 26729571
1996 Expression of the zinc finger gene EVI-1 in ovarian and other cancers. British journal of cancer 61 8932329
2020 The conserved and divergent roles of Prdm3 and Prdm16 in zebrafish and mouse craniofacial development. Developmental biology 59 32044379
2014 The role of EVI1 in myeloid malignancies. Blood cells, molecules & diseases 59 24495476
2020 Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia. Blood 57 32219447
2008 The MDS1-EVI1 gene complex as a retrovirus integration site: impact on behavior of hematopoietic cells and implications for gene therapy. Molecular therapy : the journal of the American Society of Gene Therapy 57 18227842
2002 The leukemia-associated transcription repressor AML1/MDS1/EVI1 requires CtBP to induce abnormal growth and differentiation of murine hematopoietic cells. Oncogene 57 12082639
2003 The role of EVI1 in normal and leukemic cells. Blood cells, molecules & diseases 54 12972028
1996 The chimeric genes AML1/MDS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties. Proceedings of the National Academy of Sciences of the United States of America 54 8577711
2013 EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis. Oncogene 52 23752186
2007 Repression of RUNX1 activity by EVI1: a new role of EVI1 in leukemogenesis. Cancer research 52 17575132
2021 PAX8 and MECOM are interaction partners driving ovarian cancer. Nature communications 45 33903593
2001 EVI1 expression in acute myeloid leukaemia. British journal of haematology 45 11167805
2001 The leukaemia-associated transcription factors EVI-1 and MDS1/EVI1 repress transcription and interact with histone deacetylase. British journal of haematology 45 11552981
2017 RUNX1-ETO and RUNX1-EVI1 Differentially Reprogram the Chromatin Landscape in t(8;21) and t(3;21) AML. Cell reports 42 28538183
2017 GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis. Blood 41 28630119
2019 EVI1 promotes epithelial-to-mesenchymal transition, cancer stem cell features and chemo-/radioresistance in nasopharyngeal carcinoma. Journal of experimental & clinical cancer research : CR 40 30770775
2004 Both AML1 and EVI1 oncogenic components are required for the cooperation of AML1/MDS1/EVI1 with BCR/ABL in the induction of acute myelogenous leukemia in mice. Oncogene 40 14724585
2017 Prominent Oncogenic Roles of EVI1 in Breast Carcinoma. Cancer research 37 28209621
2014 Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Oncogene 37 24747972
2023 EVI1 drives leukemogenesis through aberrant ERG activation. Blood 36 36095844
2013 EVI1 splice variants modulate functional responses in ovarian cancer cells. Molecular oncology 36 23517670
2023 Epigenetic landscape reveals MECOM as an endothelial lineage regulator. Nature communications 35 37185814
2007 Leukemogenesis of the EVI1/MEL1 gene family. International journal of hematology 35 17483069
2011 Targeting a DNA binding motif of the EVI1 protein by a pyrrole-imidazole polyamide. Biochemistry 33 22039883
2002 EVI1 is expressed in megakaryocyte cell lineage and enforced expression of EVI1 in UT-7/GM cells induces megakaryocyte differentiation. Biochemical and biophysical research communications 33 11922610
2006 Targeted degradation of the AML1/MDS1/EVI1 oncoprotein by arsenic trioxide. Cancer research 32 17145882
2021 MECOM permits pancreatic acinar cell dedifferentiation avoiding cell death under stress conditions. Cell death and differentiation 31 33762742
2003 Quantitative comparison of the expression of EVI1 and its presumptive antagonist, MDS1/EVI1, in patients with myeloid leukemia. Genes, chromosomes & cancer 31 12461752
2019 Direct interaction between the PRDM3 and PRDM16 tumor suppressors and the NuRD chromatin remodeling complex. Nucleic acids research 30 30462309
2015 EVI1 promotes tumor growth via transcriptional repression of MS4A3. Journal of hematology & oncology 30 25886616
2010 Evi-1 as a critical regulator of leukemic cells. International journal of hematology 30 20532840
2000 The EVI-1 gene--its role in pathogenesis of human leukemias. Leukemia research 30 10867128
1999 The transcription factor Evi-1. The international journal of biochemistry & cell biology 30 10641791
2011 Evi1 forms a bridge between the epigenetic machinery and signaling pathways. Oncotarget 27 21795762
2015 3q26/EVI1 rearrangements in myeloid hemopathies: a cytogenetic review. Future oncology (London, England) 26 26043219
2010 The role of Runx1/AML1 and Evi-1 in the regulation of hematopoietic stem cells. Journal of cellular physiology 26 19847803
2016 miR-133 regulates Evi1 expression in AML cells as a potential therapeutic target. Scientific reports 25 26754824
2018 t(3;8)(q26.2;q24) Often Leads to MECOM/MYC Rearrangement and Is Commonly Associated with Therapy-Related Myeloid Neoplasms and/or Disease Progression. The Journal of molecular diagnostics : JMD 24 30576868
2013 Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture. Journal of medical genetics 24 23349225
2019 EVI1 triggers metabolic reprogramming associated with leukemogenesis and increases sensitivity to L-asparaginase. Haematologica 23 31649131
2015 Functional features of EVI1 and EVI1Δ324 isoforms of MECOM gene in genome-wide transcription regulation and oncogenicity. Oncogene 23 26234679
2010 Evaluation of EVI1 and EVI1s (Delta324) as potential therapeutic targets in ovarian cancer. Gynecologic oncology 23 20462630
2024 PRDM3/16 regulate chromatin accessibility required for NKX2-1 mediated alveolar epithelial differentiation and function. Nature communications 22 39284798
2022 Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia. Blood 22 35709354
2020 EVI1 as a Marker for Lymph Node Metastasis in HNSCC. International journal of molecular sciences 22 32013033
2020 EVI1 in Leukemia and Solid Tumors. Cancers 22 32962037
2011 EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells. British journal of haematology 22 21569010
2001 Oncogenic mechanisms of Evi-1 protein. Cancer chemotherapy and pharmacology 22 11587364
2023 A distal super-enhancer activates oncogenic ETS2 via recruiting MECOM in inflammatory bowel disease and colorectal cancer. Cell death & disease 21 36609474
2020 EVI1 and GATA2 misexpression induced by inv(3)(q21q26) contribute to megakaryocyte-lineage skewing and leukemogenesis. Blood advances 21 32330245
2015 EVI1, a target gene for amplification at 3q26, antagonizes transforming growth factor-β-mediated growth inhibition in hepatocellular carcinoma. Cancer science 21 25959919
2021 Mds1CreERT2, an inducible Cre allele specific to adult-repopulating hematopoietic stem cells. Cell reports 19 34407416
2012 CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737. Experimental hematology 19 22634393
2012 EVI1 and MDS1/EVI1 expression during primary human hematopoietic progenitor cell differentiation into various myeloid lineages. Anticancer research 18 23155256
2024 Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2. Science advances 17 38748792
2022 CRISPR-mediated MECOM depletion retards tumor growth by reducing cancer stem cell properties in lung squamous cell carcinoma. Molecular therapy : the journal of the American Society of Gene Therapy 17 35733338
2020 PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response. Cell death & disease 17 32179733
2013 Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia. Blood 17 24021671
2008 Role of the RUNX1-EVI1 fusion gene in leukemogenesis. Cancer science 17 19016745
2003 Low expression of MDS1-EVI1-like-1 (MEL1) and EVI1-like-1 (EL1) genes in favorable-risk acute myeloid leukemia. Experimental hematology 17 14585371
2021 Comparison of myeloid neoplasms with nonclassic 3q26.2/MECOM versus classic inv(3)/t(3;3) rearrangements reveals diverse clinicopathologic features, genetic profiles, and molecular mechanisms of MECOM activation. Genes, chromosomes & cancer 16 34668265
2020 Emerging Roles of PRDM Factors in Stem Cells and Neuronal System: Cofactor Dependent Regulation of PRDM3/16 and FOG1/2 (Novel PRDM Factors). Cells 16 33291744
2017 The MDS and EVI1 complex locus (MECOM) isoforms regulate their own transcription and have different roles in the transformation of hematopoietic stem and progenitor cells. Biochimica et biophysica acta. Gene regulatory mechanisms 16 28391050
2013 Deletion of Mecom in mouse results in early-onset spinal deformity and osteopenia. Bone 16 24316420
1998 Comparative expression analysis of the antagonistic transcription factors EVI1 and MDS1-EVI1 in murine tissues and during in vitro hematopoietic differentiation. Biochemical and biophysical research communications 16 9837768
1996 Pattern of expression and their clinical implications of the GATA family, stem cell leukemia gene, and EVI1 in leukemia and myelodysplastic syndromes. Leukemia & lymphoma 16 9031072
2023 MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development. Journal of clinical immunology 15 37407873
2020 Receptor-like kinases MDS1 and MDS2 promote SUMM2-mediated immunity. Journal of integrative plant biology 15 32497412
2023 EVI1 exerts distinct roles in AML via ERG and cyclin D1 promoting a chemoresistant and immune-suppressive environment. Blood advances 14 36269819
2021 Identification of loci associated with susceptibility to bovine paratuberculosis and with the dysregulation of the MECOM, eEF1A2, and U1 spliceosomal RNA expression. Scientific reports 12 33432064
2018 EVI1 expression is associated with aggressive behavior in intrahepatic cholangiocarcinoma. Virchows Archiv : an international journal of pathology 12 30349952

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