{"gene":"MYB","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1991,"finding":"c-myb is required for definitive (adult-type) fetal liver hematopoiesis but not for primitive (yolk sac) erythropoiesis; homozygous c-myb knockout mice die by embryonic day 15 with severe anemia due to failure of adult-type hematopoietic progenitor cell proliferation in the fetal liver.","method":"Homologous recombination knockout in mouse embryonic stem cells; phenotypic analysis of homozygous mutant embryos","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined cellular phenotype, replicated across multiple lineages, foundational study","pmids":["1709592"],"is_preprint":false},{"year":1988,"finding":"Constitutive expression of full-length human c-myb cDNA blocks DMSO-induced erythroid differentiation of Friend murine erythroleukemia cells, establishing a causal role for c-myb in inhibiting erythroid differentiation.","method":"Stable transfection of c-myb expression construct into F-MEL cells; differentiation assay with DMSO; methotrexate amplification of transgene","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in cell line with defined differentiation phenotype, single lab","pmids":["2832742"],"is_preprint":false},{"year":1996,"finding":"CBP (CREB-binding protein) is a direct transcriptional coactivator of c-Myb; CBP binds the transactivation domain of c-Myb in a phosphorylation-independent manner in vitro, and a c-Myb/CBP complex forms in vivo (yeast two-hybrid). CBP stimulates c-Myb-dependent transcription, and adenovirus E1A (which binds CBP) inhibits c-Myb-induced transactivation.","method":"In vitro GST pulldown, yeast two-hybrid, transactivation reporter assays, antisense CBP inhibition, E1A competition assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vitro binding, two-hybrid, functional reporter assays), single lab with rigorous controls","pmids":["8598284"],"is_preprint":false},{"year":2005,"finding":"c-Myb controls hematopoietic stem cell proliferation and differentiation through interaction with the transcriptional coactivator p300; a point mutation (M303V) in the c-Myb transactivation domain disrupts its interaction with p300, causing thrombocytosis, anemia, lymphopenia, absence of eosinophils, and a 10-fold increase in cycling HSCs.","method":"ENU mutagenesis screen; identification of M303V point mutation; co-immunoprecipitation of c-Myb/p300; transactivation assays; hematopoietic phenotyping; cell cycle analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined point mutation disrupting specific protein interaction linked to precise in vivo phenotype, multiple orthogonal methods","pmids":["15691758"],"is_preprint":false},{"year":1998,"finding":"Pim-1 kinase binds to p100 (a c-Myb transcriptional coactivator) via yeast two-hybrid, phosphorylates p100 in vitro, forms a stable complex with p100 in animal cells, and stimulates c-Myb transcriptional activity in a p100-dependent manner downstream of Ras signaling.","method":"Yeast two-hybrid screen; in vitro kinase assay; co-immunoprecipitation; transactivation reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid, in vitro phosphorylation, co-IP, and functional reporter assays in single study with multiple orthogonal methods","pmids":["9809063"],"is_preprint":false},{"year":1996,"finding":"The EVES motif in the c-Myb C-terminus mediates intramolecular interaction with the N-terminal DNA-binding domain (via yeast two-hybrid), and also interacts intermolecularly with p100 coactivator. The EVES motif contains a phosphorylation site implicated in negative regulation of c-Myb activity.","method":"Yeast two-hybrid assay; domain mapping; identification of EVES motif; functional coactivation assays","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus functional assays, single lab","pmids":["8756344"],"is_preprint":false},{"year":1996,"finding":"c-Myb, C/EBPalpha, and PU.1 cooperate to activate the neutrophil elastase (NE) promoter through binding to their respective cis elements; cooperative activation is mediated via DNA-binding sites and likely involves a coactivator protein, as synergistic DNA binding between the factors could not be demonstrated in gel shift assays.","method":"Transient transfection reporter assays; gel shift (EMSA); mutational analysis of promoter elements; cell-line-specific assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell lines, functional mutagenesis, single lab","pmids":["8756629"],"is_preprint":false},{"year":2002,"finding":"Crystal structures of c-Myb DBD and C/EBPbeta DBD bound to promoter DNA revealed that C/EBPbeta interacts with R2 of c-Myb bound to a separate DNA fragment, with intervening DNA looping; point mutations in v-Myb R2 eliminate this interaction. GST pulldown and AFM confirmed long-range protein-protein interaction and DNA looping.","method":"X-ray crystallography; GST pulldown; luciferase transactivation assay; atomic force microscopy","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus multiple orthogonal biochemical validations (GST pulldown, AFM, functional assays)","pmids":["11792321"],"is_preprint":false},{"year":2004,"finding":"Wnt-1 signal induces phosphorylation and proteasome-dependent degradation of c-Myb via the TAK1–HIPK2–NLK kinase cascade; NLK binds directly to c-Myb together with HIPK2, leading to c-Myb phosphorylation at multiple sites, followed by ubiquitination and degradation. Overexpression of NLK in M1 cells abrogates c-Myb's ability to maintain the undifferentiated state.","method":"Co-immunoprecipitation; in vitro kinase assays; proteasome inhibitor experiments; ubiquitination assays; M1 cell differentiation assay; overexpression studies","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, in vitro kinase, ubiquitination, functional differentiation assay) in single rigorous study","pmids":["15082531"],"is_preprint":false},{"year":2000,"finding":"p300 acetylates c-Myb at three lysine residues (K471, K480, K485) in the carboxyl-terminal conserved domain both in vitro and in vivo; acetylation dramatically increases c-Myb DNA binding activity and transactivation of mim-1 and CD34 promoters. The bromodomain of p300 is required for effective acetylation of c-Myb.","method":"In vitro acetyltransferase assay; in vivo acetylation detection; EMSA; luciferase reporter assay; site-directed mutagenesis (KA mutant)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro and in vivo acetylation demonstrated, mutagenesis of specific sites, functional consequences measured with multiple assays","pmids":["10656693"],"is_preprint":false},{"year":2000,"finding":"CBP acetylates c-Myb at K438 and K441 within its negative regulatory domain (NRD) in vitro, and in vivo at those and additional p300-induced sites; acetylation of these sites enhances c-Myb's association with CBP and synergistically increases c-Myb transactivation activity. The C/H2 domain of CBP directly interacts with the NRD of c-Myb.","method":"In vitro acetyltransferase assay; site-directed mutagenesis; transactivation reporter assays; co-immunoprecipitation; domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzyme assay, site-specific mutagenesis, in vivo validation, functional assays","pmids":["11073948"],"is_preprint":false},{"year":1986,"finding":"The human c-myb gene product localizes to the nucleus and is associated with the nuclear matrix in leukemic cells.","method":"Immunostaining with antiserum generated against recombinant c-myb carboxyl-terminal protein; nuclear fractionation","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization by immunostaining, replicated across multiple samples","pmids":["3014652"],"is_preprint":false},{"year":1988,"finding":"c-myb protein degradation is energy-dependent, does not involve lysosomes or ubiquitin, and does not produce cleavage intermediates; heat shock increases c-myb protein half-life ~2-fold and reduces c-myb protein synthesis ~4-fold, with recovery being energy-dependent.","method":"Pulse-chase metabolic labeling; inhibitor studies (lysosomal, energy, ubiquitin); heat shock experiments; protein synthesis measurement","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic inhibitor studies and pulse-chase, single lab","pmids":["3043180"],"is_preprint":false},{"year":1993,"finding":"c-myb transactivates the human cdc2 gene promoter through two closely spaced Myb binding sites at -410 to -392 upstream of the transcription start site; mutations in the Myb binding sites abrogate c-myb-dependent CAT reporter activation.","method":"CAT reporter cotransfection; mutational analysis of Myb binding sites; electrophoretic mobility shift assay with bacterially expressed Myb protein","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis of promoter, EMSA, functional reporter, single lab","pmids":["8420994"],"is_preprint":false},{"year":1991,"finding":"Truncation of either the amino or carboxyl terminus of c-Myb is sufficient for transformation of chicken bone marrow cells; full-length c-Myb overexpression does not transform. The normal N- and C-termini of c-Myb suppress transformation when fused to v-Myb.","method":"Retroviral expression of truncated c-Myb constructs; transformation assay of primary chicken bone marrow cells; clonogenic assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic domain truncation analysis with primary cell transformation assay, multiple constructs tested","pmids":["2072904"],"is_preprint":false},{"year":2010,"finding":"c-Myb is recruited to the MLL histone methyltransferase complex through menin, contributing to MLL-mediated H3K4 methylation; silencing MYB in human leukemic cells causes global decrease in H3K4 methylation, decreased HOXA9 and MEIS1 expression, and reduced MLL and menin occupancy at the HOXA9 locus.","method":"Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); siRNA-mediated knockdown; methylation assays; H3K4me3 quantification","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, ChIP, and functional epistasis with multiple orthogonal methods","pmids":["20093773"],"is_preprint":false},{"year":1993,"finding":"c-Myb directly transactivates c-myc in a cell-lineage-dependent manner requiring direct DNA binding by Myb to Myb-binding sites in the c-myc promoter; de novo protein synthesis is not required for c-myc transactivation.","method":"Transient transfection reporter assays; S1 nuclease protection; mutational analysis; conditional c-Myb expression; cycloheximide inhibition","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell lines, promoter mutagenesis, conditional expression system, single lab","pmids":["8474446"],"is_preprint":false},{"year":1994,"finding":"c-Myb transactivates the CD34 promoter via specific Myb binding sites in the 5' flanking region; constitutive c-Myb expression induces endogenous CD34 mRNA and surface antigen in CD34-negative glioblastoma cells.","method":"CAT reporter transfection; EMSA; northern blot; c-Myb overexpression in fibroblasts and glioblastoma cells","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter-binding and functional reporter assays, induction of endogenous gene, single lab","pmids":["7509358"],"is_preprint":false},{"year":1998,"finding":"c-Maf physically associates with c-Myb and inhibits c-Myb-dependent transcription of the myeloid CD13/APN gene promoter; formation of inhibitory Myb-Maf complexes is developmentally regulated, highest in immature myeloid cells.","method":"Co-immunoprecipitation; reporter gene assays; western blot; developmental stage-specific cell line analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus functional reporter assays replicated across developmental stages","pmids":["9566892"],"is_preprint":false},{"year":2005,"finding":"TRAF7 binds to the DNA-binding domain of c-Myb via its WD40 repeats and stimulates c-Myb sumoylation at K523 and K499 (same sites as PIASy-induced sumoylation); sumoylated c-Myb is sequestered to the cytoplasm by TRAF7, inhibiting c-Myb transactivation activity.","method":"Co-immunoprecipitation; sumoylation assay; immunofluorescence localization; subcellular fractionation; transactivation reporter assays; site-directed mutagenesis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, defined sumoylation sites by mutagenesis, subcellular fractionation/localization, functional consequences all demonstrated","pmids":["16162816"],"is_preprint":false},{"year":2007,"finding":"c-Myb directly activates Gata3 transcription, and is required for upregulation of Gata3 in response to TCR signaling during positive selection; loss of c-Myb causes fewer helper T cells and gain-of-function c-Myb transgene blocks cytotoxic T cell development.","method":"Conditional c-Myb knockout and c-Myb transgenic mice; reporter gene assays demonstrating Gata3 as direct c-Myb target; flow cytometric analysis of T cell development","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic gain and loss of function plus direct target gene validation with reporter assays","pmids":["17641686"],"is_preprint":false},{"year":2010,"finding":"c-myb directly transactivates KLF1 and LMO2 promoters (demonstrated by ChIP and luciferase reporter assay) to support erythropoiesis; c-myb silencing in human CD34+ cells shifts fate toward megakaryocyte at expense of erythroid lineage, and this defect is rescued by KLF1 or LMO2 overexpression.","method":"siRNA knockdown; chromatin immunoprecipitation; luciferase reporter assay; retroviral rescue experiments; clonogenic assay; flow cytometry","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP + reporter assay + genetic rescue with multiple orthogonal methods","pmids":["20686118"],"is_preprint":false},{"year":2007,"finding":"miR-150 controls B cell differentiation by targeting c-Myb in a dose-dependent manner; gain and loss of miR-150 show that its effect on lymphocyte development is mediated through c-Myb, with combined c-Myb conditional/partial ablation confirming the miR-150–c-Myb epistasis.","method":"miR-150 loss-of-function (knockout) and gain-of-function (transgenic) mouse models; conditional c-Myb ablation; flow cytometric analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic manipulation of both miR and target in vivo, confirmed epistasis","pmids":["17923094"],"is_preprint":false},{"year":2019,"finding":"c-Myb acts as a transcriptional activator of Tcf7 (Tcf1) to enhance CD8+ T cell memory development and as a repressor of Zeb2 to inhibit effector differentiation; the transactivation domain is necessary for restraining differentiation while the negative regulatory domain is critical for cell survival.","method":"Conditional c-Myb knockout; c-Myb overexpression; domain mutagenesis experiments; adoptive transfer; viral infection models; gene expression analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis plus KO and overexpression with defined molecular targets, multiple orthogonal methods","pmids":["30778251"],"is_preprint":false},{"year":2010,"finding":"c-Myb promotes survival of CD4+CD8+ double-positive thymocytes by upregulating Bcl-xL; conditional deletion causes premature apoptosis of small preselection DP thymocytes independently of TCR signaling, and forced Bcl-xL expression rescues survival while c-Myb re-expression restores both Bcl-xL expression and the DP compartment.","method":"Conditional c-Myb knockout; Bcl-xL retroviral rescue; c-Myb retroviral rescue; apoptosis assays; Tcra repertoire analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue with both Bcl-xL and c-Myb, multiple orthogonal validations","pmids":["20142358"],"is_preprint":false},{"year":1999,"finding":"c-Myb is required for early T cell development; deletion of c-Myb causes a complete block just before the oligopotent thymocyte matures into the definitive T cell precursor.","method":"Homozygous null c-Myb/Rag1 chimeric mice; flow cytometric analysis of thymocyte populations","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic chimeric mouse model with defined developmental block","pmids":["10323859"],"is_preprint":false},{"year":2005,"finding":"c-Myb is required for B cell development at the pro-B to pre-B cell transition; loss of c-Myb prevents normal B cell homeostasis by decreasing splenic B cell survival, associated with hyporesponsiveness to BLyS, decreased BR3 expression, and altered PKCdelta nuclear accumulation.","method":"Tissue-specific (conditional) Myb inactivation; flow cytometry; survival assays; BLyS receptor expression analysis; PKCdelta localization studies","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined molecular pathway components, multiple orthogonal methods","pmids":["16169500"],"is_preprint":false},{"year":2009,"finding":"c-Myb is absolutely required for differentiation of CD19+ B-lineage cells, controlling intrinsic survival and proper expression of IL-7 receptor alpha (CD127) and Ebf1; survival of c-Myb-deficient pro-B cells cannot be rescued by CD127 retroviral transduction, but B cell differentiation can be partially rescued by exogenous Ebf1.","method":"Tissue-specific Myb inactivation (Mb1-cre); retroviral rescue experiments; stromal cell culture; flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, rescue experiments distinguishing CD127-dependent and -independent pathways","pmids":["19843942"],"is_preprint":false},{"year":2002,"finding":"c-Myb and Pax-5 cooperatively bind to and activate the RAG-2 promoter in immature B cells through synergistic DNA binding; the C-terminus of c-Myb mediates physical interaction with Pax-5, and dominant-negative c-Myb suppresses RAG-2 promoter activity.","method":"Reporter gene assays; EMSA; co-immunoprecipitation; dominant-negative mutant experiments; deletion analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA, co-IP, functional reporter with dominant-negative, single lab","pmids":["11781241"],"is_preprint":false},{"year":1993,"finding":"Casein kinase II (CKII) phosphorylates c-Myb at Ser-11 and Ser-12; replacing these serines with alanine increases DNA-binding affinity (up to 10-fold reduced dissociation constant) and increases transactivation activity on mim-1 and synthetic promoters.","method":"In vitro kinase assay; site-directed mutagenesis; EMSA with dissociation constant measurement; transactivation reporter assays","journal":"Cellular & molecular biology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus mutagenesis and functional assays, single lab","pmids":["7735324"],"is_preprint":false},{"year":1993,"finding":"p42mapk (ERK2) phosphorylates avian and murine c-Myb but not AMV v-Myb in vitro on serine and threonine residues mapping to the C-terminal negative regulatory domain.","method":"In vitro kinase assay with bacterially expressed Myb proteins; phosphoamino acid analysis; deletion mapping","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay with domain mapping, single lab","pmids":["8336948"],"is_preprint":false},{"year":2000,"finding":"Phosphorylation of c-Myb by Ser/Thr kinases (inhibited by okadaic acid) leads to hyperphosphorylation causing conformational changes and extremely rapid proteasome-dependent degradation; Ser/Thr phosphatases normally prevent the conformational changes that target c-Myb for degradation. The hyperphosphorylated form retains DNA binding activity.","method":"Okadaic acid phosphatase inhibitor treatment; pulse-chase protein stability assay; proteasome inhibitor; EMSA; phosphoamino acid analysis; antibody conformational recognition assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical inhibitor studies with pulse-chase and EMSA, single lab","pmids":["10851088"],"is_preprint":false},{"year":2017,"finding":"Mebendazole induces c-MYB protein degradation via the proteasome by interfering with the HSP70 chaperone system, inhibiting AML colony formation in vitro and AML progression in mouse xenotransplantation in vivo.","method":"Proteasome inhibitor rescue experiments; HSP70 inhibition assays; colony formation assay; mouse xenotransplantation; gene expression signature analysis","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic studies with proteasome/HSP70 inhibitors plus functional colony assay and in vivo model, single lab","pmids":["29089643"],"is_preprint":false},{"year":2022,"finding":"Withaferin A (WFA) induces rapid c-MYB protein ablation by disrupting HSP70/HSC70 chaperone protein homeostasis via proteotoxicity and the unfolded protein response; anti-AML activity of WFA depends on c-MYB modulation and can be partially reversed by a stabilized c-MYB mutant.","method":"Proteasome inhibitor rescue; stabilized c-MYB mutant rescue; western blot; colony formation assay; disease progression assay","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic rescue with stabilized mutant plus chaperone pathway dissection, single lab","pmids":["35368048"],"is_preprint":false},{"year":2008,"finding":"Pin1 physically interacts with c-Myb in a phosphorylation-dependent manner at S528 (within the EVES motif), and this interaction increases c-Myb transactivation activity in a manner dependent on Pin1 catalytic activity; Pin1 interaction does not increase c-Myb DNA binding.","method":"Co-immunoprecipitation; site-directed mutagenesis; transactivation reporter assays; DNA-binding assays; mass spectrometry confirming S528 phosphorylation in vivo","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP in physiological cell line, site-specific mutagenesis, in vivo phosphorylation by MS, functional assays","pmids":["18359295"],"is_preprint":false},{"year":2000,"finding":"c-Myb and GATA-1 mutually inhibit each other's transcriptional activity through competitive binding to CBP; c-Myb, GATA-1, and CBP can form bipartite complexes but not a tripartite complex, with exclusive CBP binding being the molecular basis for mutual inhibition.","method":"Co-immunoprecipitation; transactivation reporter assays; domain mapping","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus reporter assays, single lab, multiple pairwise interactions tested","pmids":["10644988"],"is_preprint":false},{"year":2010,"finding":"c-myb loss-of-function (missense I181N in the DNA recognition helix of repeat 3) in zebrafish abolishes definitive hematopoiesis while leaving primitive hematopoiesis intact, confirming evolutionary conservation of c-myb's essential role in definitive hematopoiesis across vertebrates.","method":"ENU mutagenesis; identification of c-myb(t25127) missense allele; zebrafish phenotypic analysis; genetic complementation","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function allele with specific domain-disrupting mutation, confirms mechanistic conservation","pmids":["20823231"],"is_preprint":false},{"year":2008,"finding":"c-Myb-null embryonic stem cells fail to produce embryoid bodies with spontaneously contracting smooth muscle cells; mesodermal differentiation is unaffected but myocardin upregulation and SMC-specific gene expression (smooth muscle alpha-actin, SM22alpha, SMMHC) are impaired; c-myb-/- cells show reduced contribution to SMC lineage in chimeric embryos and aortas.","method":"c-myb-/- ES cell differentiation to embryoid bodies; RT-PCR; flow cytometry; chimeric embryo analysis; aorta chimerism assessment","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined molecular (myocardin) and cellular (SMC differentiation) phenotype, in vitro and in vivo","pmids":["18187733"],"is_preprint":false},{"year":2007,"finding":"c-Myb is required for normal progenitor cell homeostasis in colonic crypts; hypomorphic c-myb mutations targeting DNA binding, transactivation, or negative regulatory domains all reduce colonic crypt size through a progenitor proliferation defect mediated in part by reduced Cyclin E1 expression; tissue-specific adult colon deletion confirms requirement for crypt integrity and differentiation.","method":"Three distinct hypomorphic c-myb mouse strains; tissue-specific adult colon c-myb deletion; BrdU proliferation assay; cyclin E1 expression analysis","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent alleles plus conditional deletion, molecular target (Cyclin E1) identified","pmids":["17360438"],"is_preprint":false},{"year":2017,"finding":"c-Myb activates the miR-200 family (miR-200b, miR-200a, miR-429, miR-200c, miR-141) by binding to Myb binding sites in their promoter regions; when co-expressed with ZEB1, ZEB1 repression dominates over c-Myb activation; promoter methylation during TGF-β-induced EMT overrides c-Myb-dependent activation.","method":"Ectopic expression and gene silencing; luciferase reporter assay with Myb binding site mutations; ChIP; bisulfite sequencing","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay with site mutagenesis, single lab","pmids":["24067373"],"is_preprint":false},{"year":2008,"finding":"Alternative splicing of human c-myb produces a family of transcripts (using alternate exons 8A, 9A, 9B, 10A, 13A, 14A) encoding c-Myb proteins with identical DNA binding domains but unique C-terminal domains; these variant proteins exhibit quantitative and qualitative differences in transcriptional activities and specificities.","method":"Quantitative RT-PCR; polysome association assay; transactivation reporter assays; expression analysis in human leukemia samples","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with defined splice variants, single lab","pmids":["18195038"],"is_preprint":false},{"year":2017,"finding":"c-Myb represses T-bet expression in mature B cells to limit aberrant IgG2c/CXCR3/plasma cell differentiation during germinal center responses; deletion of c-Myb increases T-bet expression and results in aberrant plasma cell differentiation within the germinal center mediated by CXCR3.","method":"Conditional c-Myb deletion in mature B cells; flow cytometry; serum Ig quantification; gene expression analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional genetic deletion with defined molecular pathway, single lab","pmids":["28423310"],"is_preprint":false},{"year":2015,"finding":"c-Myb is required for plasma cell migration to bone marrow; in the absence of c-Myb, c-Myb-deficient plasma cells fail to migrate along a CXCL12 gradient, resulting in absence of IgG+ antigen-specific plasma cells in bone marrow after immunization or infection.","method":"Conditional c-Myb deletion; in vitro migration assay to CXCL12; immunization and viral infection models; flow cytometry","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined molecular mechanism (CXCL12 chemokine response), in vitro migration assay, in vivo confirmation","pmids":["26077717"],"is_preprint":false},{"year":2011,"finding":"c-Myb binds the Bmi1 promoter and activates its transcription; c-Myb and Bmi1 are required for p190BCR/ABL-dependent B-cell leukemogenesis, and ectopic Bmi1 expression can partially rescue the proliferative defect caused by c-Myb loss.","method":"Co-immunoprecipitation; ChIP; luciferase reporter assay; knockdown; retroviral rescue; in vivo leukemia model","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay for direct target, genetic rescue experiments, single lab","pmids":["21960247"],"is_preprint":false},{"year":2017,"finding":"c-Myb functions as a pioneer transcription factor; each repeat of the c-Myb DNA-binding domain binds histones, and the D152V mutation in repeat 3 disrupts histone binding, impairs chromatin opening (ATAC-seq), and abrogates c-Myb's ability to regulate differentiation-associated genes.","method":"ATAC-seq; histone binding assay; site-directed mutagenesis (D152V); transcriptome analysis; chromatin accessibility assay in K562 cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide chromatin accessibility assay (ATAC-seq) plus biochemical histone binding and mutagenesis, multiple orthogonal methods","pmids":["28472346"],"is_preprint":false},{"year":1996,"finding":"An intact c-Myb binding site in the TCR-delta intronic enhancer (Edelta) is necessary for efficient VDJ recombination at the TCR-delta locus in vivo; transgenic minilocus recombination substrate with mutated Myb binding site in Edelta shows markedly reduced rearrangement.","method":"Transgenic mouse minilocus recombination substrate; mutation of Myb binding site in Edelta; PCR analysis of VDJ rearrangements","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic experiment with site-specific mutagenesis and direct measurement of recombination","pmids":["8551234"],"is_preprint":false},{"year":1995,"finding":"Phosphorylation of c-Myb at Ser-11 and Ser-12 positively modulates DNA binding by overcoming the negative regulatory influence of the leucine zipper (LZ); LZ mutation or phosphorylation both enhance DNA binding activity, and phosphatase treatment reduces DNA binding of insect-cell-expressed c-Myb.","method":"In vitro binding assays with E. coli-expressed c-Myb proteins; CKII and PKA kinase assays; phosphatase treatment; insect cell expression; site-directed mutagenesis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro phosphorylation and binding assays with multiple expression systems, single lab","pmids":["7478531"],"is_preprint":false}],"current_model":"c-Myb is a nuclear sequence-specific transcription factor (recognizing C/T-AAC-G/T-G) that functions as an essential regulator of definitive hematopoiesis and multiple immune cell lineages; its transcriptional activity is controlled by a network of post-translational modifications (phosphorylation by CKII, p42mapk, and the TAK1–HIPK2–NLK cascade; acetylation by p300 and CBP at defined lysines; sumoylation by TRAF7/PIASy targeting to the cytoplasm; proteasome-dependent degradation triggered by hyperphosphorylation), by intramolecular interactions between its EVES-containing negative regulatory domain and its N-terminal DNA-binding domain, and by direct binding of coactivators (CBP, p300, p100) and repressors (GATA-1, c-Maf, ZEB); it acts as a pioneer transcription factor whose DBD binds histones and opens chromatin at target loci including cdc2, CD34, KLF1, LMO2, Bcl-xL, Gata3, Bmi1, and miR-200 family members, and its activity is regulated post-transcriptionally by miR-150 and miR-126 that target its 3'UTR."},"narrative":{"mechanistic_narrative":"c-Myb is a nuclear, nuclear-matrix-associated sequence-specific transcription factor that serves as a master regulator of definitive hematopoiesis: genetic ablation in mice abolishes adult-type fetal liver hematopoiesis while sparing primitive yolk-sac erythropoiesis [PMID:1709592, PMID:3014652], a requirement conserved to zebrafish where a DNA-recognition-helix mutation in repeat 3 selectively eliminates definitive blood [PMID:20823231]. Its DNA-binding domain functions as a pioneer factor whose repeats bind histones and open chromatin, an activity destroyed by the D152V mutation in repeat 3 [PMID:28472346]. Through direct binding to Myb sites, c-Myb activates a broad differentiation-associated target program including cdc2, c-myc, CD34, KLF1, LMO2, Bmi1, Gata3, Tcf7, and the miR-200 family, and represses Zeb2 and T-bet [PMID:8420994, PMID:8474446, PMID:7509358, PMID:20686118, PMID:21960247, PMID:17641686, PMID:30778251, PMID:24067373, PMID:28423310]; it balances erythroid versus megakaryocytic fate (via KLF1/LMO2) and stage-specific lymphoid programs, and supports thymocyte survival by inducing Bcl-xL [PMID:20686118, PMID:20142358]. c-Myb governs successive checkpoints across the immune system — early T-cell maturation, the pro-B to pre-B transition and B-lineage survival, RAG-2-dependent recombination, helper/cytotoxic T fate, CD8 memory, and CXCL12-dependent plasma cell homing to bone marrow [PMID:10323859, PMID:16169500, PMID:19843942, PMID:11781241, PMID:8551234, PMID:17641686, PMID:30778251, PMID:26077717] — and also controls colonic crypt progenitor proliferation and smooth-muscle differentiation, extending its role beyond blood [PMID:17360438, PMID:18187733]. Transcriptional output is set by coactivator recruitment: CBP and p300 bind the transactivation/negative regulatory domain and acetylate defined C-terminal lysines to boost DNA binding and activity, with the p300-interacting M303V mutation deranging HSC homeostasis [PMID:8598284, PMID:10656693, PMID:11073948, PMID:15691758]; c-Myb competes with GATA-1 for CBP and is antagonized by c-Maf and ZEB1 [PMID:10644988, PMID:9566892, PMID:24067373]. c-Myb is integrated into chromatin machinery by joining the menin/MLL complex to promote H3K4 methylation at HOXA9 [PMID:20093773]. Its abundance and activity are tuned by an intramolecular EVES-domain autoinhibition relieved by Pin1 and p100 [PMID:8756344, PMID:18359295, PMID:9809063], by phosphorylation (CKII at Ser-11/12 enhancing DNA binding, the Wnt-driven TAK1–HIPK2–NLK cascade and hyperphosphorylation driving proteasomal degradation) [PMID:7735324, PMID:7478531, PMID:15082531, PMID:10851088], and by TRAF7-stimulated sumoylation that sequesters it to the cytoplasm [PMID:16162816]; oncogenic activation requires N- or C-terminal truncation that removes these autoinhibitory controls [PMID:2072904], and chaperone-disrupting drugs that destabilize c-Myb are anti-leukemic [PMID:29089643, PMID:35368048].","teleology":[{"year":1986,"claim":"Establishing that the c-myb product is a nuclear, matrix-associated protein placed it in the compartment where it could act transcriptionally.","evidence":"Immunostaining and nuclear fractionation in leukemic cells","pmids":["3014652"],"confidence":"Medium","gaps":["Did not define DNA-binding specificity or target genes","Nuclear matrix association not linked to function"]},{"year":1988,"claim":"Gain-of-function showed c-myb actively blocks differentiation, framing it as a differentiation-suppressing regulator rather than a passive marker.","evidence":"Constitutive c-myb expression in DMSO-treated Friend erythroleukemia cells","pmids":["2832742"],"confidence":"Medium","gaps":["Mechanism of differentiation block not defined","Direct target genes not identified"]},{"year":1988,"claim":"Characterizing c-myb protein turnover as energy-dependent and ubiquitin-independent opened the question of how its abundance is controlled.","evidence":"Pulse-chase with lysosomal/energy/ubiquitin inhibitors and heat shock","pmids":["3043180"],"confidence":"Medium","gaps":["Degradation pathway not molecularly identified","Later work implicated proteasome, partly contradicting ubiquitin-independence"]},{"year":1991,"claim":"Knockout and truncation analyses defined c-myb's essential physiological role in definitive hematopoiesis and revealed that its termini are autoinhibitory checkpoints whose removal causes transformation.","evidence":"Mouse c-myb knockout embryos; retroviral expression of truncated c-Myb in chicken bone marrow transformation assay","pmids":["1709592","2072904"],"confidence":"High","gaps":["Direct hematopoietic target genes not yet mapped","Mechanism by which termini suppress transformation undefined"]},{"year":1993,"claim":"Identification of direct promoter targets (cdc2, c-myc, CD34) and CKII phosphorylation established c-Myb as a sequence-specific activator whose DNA binding is post-translationally tuned.","evidence":"Reporter assays with Myb-site mutagenesis, EMSA, in vitro CKII kinase assay","pmids":["8420994","8474446","7509358","7735324"],"confidence":"Medium","gaps":["In vivo occupancy not demonstrated at this stage","Physiological kinases acting on Ser-11/12 in cells unclear"]},{"year":1996,"claim":"Discovery of CBP/p100 coactivation and the autoinhibitory EVES motif defined the dual control of c-Myb activity by coactivator recruitment and intramolecular folding, and showed combinatorial promoter activation with C/EBPalpha and PU.1.","evidence":"Yeast two-hybrid, GST pulldown, reporter and coactivation assays; cooperative neutrophil elastase promoter activation","pmids":["8598284","8756344","8756629"],"confidence":"High","gaps":["How EVES autoinhibition is relieved physiologically not yet known","Synergistic DNA binding with C/EBPalpha/PU.1 not demonstrable in EMSA"]},{"year":1998,"claim":"Pim-1 phosphorylation of p100 and c-Maf antagonism linked c-Myb activity to upstream Ras signaling and to lineage-specific repression.","evidence":"Yeast two-hybrid, in vitro kinase, co-IP, reporter assays; c-Maf co-IP and CD13 promoter assays","pmids":["9809063","9566892"],"confidence":"High","gaps":["Direct phosphorylation target on c-Myb itself not shown for Pim-1","Structural basis of Myb-Maf repression unresolved"]},{"year":1999,"claim":"Conditional and chimeric genetics pinpointed c-Myb as required at a specific early T-cell maturation checkpoint, refining its hematopoietic role to discrete developmental transitions.","evidence":"c-Myb-null/Rag1 chimeric mice with flow cytometric staging","pmids":["10323859"],"confidence":"High","gaps":["Target genes controlling this transition not identified","Cell-intrinsic vs niche contribution not fully separated"]},{"year":2000,"claim":"Acetylation by p300/CBP at defined C-terminal lysines and competitive CBP sequestration by GATA-1 established acetylation and coactivator competition as quantitative tuners of c-Myb output, while phosphorylation-driven hyperphosphorylation linked activity to proteasomal turnover.","evidence":"In vitro/in vivo acetyltransferase assays with site mutants, EMSA, co-IP; okadaic acid and proteasome inhibitor pulse-chase","pmids":["10656693","11073948","10644988","10851088"],"confidence":"High","gaps":["Identity of physiological degradation-triggering kinases not defined here","Crosstalk between acetylation and phosphorylation undefined"]},{"year":2002,"claim":"Crystallography of the c-Myb DBD with C/EBPbeta and cooperative binding with Pax-5 revealed long-range protein-protein interactions and DNA looping as a mechanism for combinatorial target activation.","evidence":"X-ray crystallography, GST pulldown, AFM; EMSA, co-IP and reporter assays at the RAG-2 promoter","pmids":["11792321","11781241"],"confidence":"High","gaps":["In vivo prevalence of DNA looping unknown","Generalizability beyond these partners untested"]},{"year":2004,"claim":"The Wnt-1/TAK1–HIPK2–NLK cascade was defined as a signaling route that phosphorylates and degrades c-Myb to permit differentiation, connecting developmental signaling to c-Myb stability.","evidence":"Co-IP, in vitro kinase, ubiquitination and proteasome assays, M1 differentiation","pmids":["15082531"],"confidence":"High","gaps":["Precise phosphodegron residues not fully mapped","E3 ligase mediating degradation not identified"]},{"year":2005,"claim":"A p300-interaction-disrupting point mutation (M303V) and TRAF7-driven sumoylation tied specific molecular interfaces to HSC homeostasis and to cytoplasmic sequestration, while B-cell genetics defined the pro-B to pre-B requirement.","evidence":"ENU M303V allele with HSC phenotyping; TRAF7 co-IP, sumoylation, fractionation; conditional B-cell Myb inactivation","pmids":["15691758","16162816","16169500"],"confidence":"High","gaps":["How sumoylation and acetylation are coordinated unclear","Direct B-cell survival target genes not all identified"]},{"year":2007,"claim":"Direct activation of Gata3 in T cells, miR-150 targeting of c-Myb in B cells, and the colonic crypt requirement extended c-Myb's regulatory logic to lineage specification, post-transcriptional control, and non-hematopoietic progenitors.","evidence":"Conditional KO/transgenic mice, reporter assays; miR-150 gain/loss with c-Myb epistasis; hypomorphic alleles and colon deletion with Cyclin E1 readout","pmids":["17641686","17923094","17360438"],"confidence":"High","gaps":["Full target networks downstream of Gata3/Cyclin E1 not mapped","miR-150 regulation in other lineages incompletely defined"]},{"year":2008,"claim":"Pin1 isomerization at the EVES motif, alternative C-terminal splicing, and the smooth-muscle differentiation requirement diversified the understanding of how c-Myb activity and specificity are generated.","evidence":"Co-IP/MS at S528 with reporter assays; RT-PCR and functional assays of splice variants; c-myb-/- ES cell SMC differentiation","pmids":["18359295","18195038","18187733"],"confidence":"Medium","gaps":["Functional consequences of individual splice variants in vivo unclear","Pin1-EVES axis link to degradation not resolved"]},{"year":2010,"claim":"Integration into the menin/MLL complex and direct KLF1/LMO2 activation defined how c-Myb shapes chromatin state and erythroid-versus-megakaryocyte fate, while the zebrafish allele confirmed evolutionary conservation of its definitive-hematopoiesis role.","evidence":"Reciprocal co-IP, ChIP, knockdown with H3K4me readout; ChIP/reporter with KLF1/LMO2 rescue; zebrafish ENU missense allele; conditional thymocyte Bcl-xL rescue","pmids":["20093773","20686118","20823231","20142358"],"confidence":"High","gaps":["Stoichiometry/architecture of c-Myb within the MLL complex undefined","Genome-wide co-occupancy with menin/MLL not fully mapped"]},{"year":2017,"claim":"Demonstration that the c-Myb DBD binds histones and opens chromatin defined it mechanistically as a pioneer factor, and chaperone-disrupting drugs revealed its therapeutic vulnerability in AML.","evidence":"ATAC-seq, histone binding, D152V mutagenesis in K562; mebendazole/HSP70 and miR-200 ChIP/reporter; T-bet repression in B cells","pmids":["28472346","29089643","24067373","28423310"],"confidence":"High","gaps":["Genome-wide rules for pioneer-mode site selection incomplete","Whether chaperone-dependent stability is leukemia-selective unclear"]},{"year":2019,"claim":"Domain-resolved genetics in CD8 T cells separated c-Myb's transactivation function (restraining effector differentiation via Tcf7/Zeb2) from its negative regulatory domain's survival function, and earlier work tied it to plasma cell homing and B-lineage survival programs.","evidence":"Conditional KO, overexpression, domain mutants, adoptive transfer and infection; CXCL12 migration assay; Ebf1/CD127 rescue in pro-B cells","pmids":["30778251","26077717","19843942"],"confidence":"High","gaps":["How the NRD promotes survival mechanistically undefined","Direct survival target genes downstream of the NRD unknown"]},{"year":null,"claim":"How the layered post-translational code (phosphorylation, acetylation, sumoylation, isomerization), EVES autoinhibition, and pioneer chromatin engagement are integrated in real time to select context-specific target programs across lineages remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking modification state to genome-wide occupancy","E3 ligase(s) and full phosphodegron for proteasomal turnover unidentified","Quantitative contribution of splice variants to lineage-specific output unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[13,16,20,21,23,39,41,44]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[7,13,17,29,44,46]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[44]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[13,16,17,21,39,43]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,36,37,38]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[20,22,23,24,25,26,27,28,41,42,45]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[15,44]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,9,10,19,31,32,33]}],"complexes":["menin/MLL histone methyltransferase complex"],"partners":["CREBBP","EP300","TRAF7","GATA1","MAF","MEN1","PIN1","PAX5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10242","full_name":"Transcriptional activator Myb","aliases":["Proto-oncogene c-Myb"],"length_aa":640,"mass_kda":72.3,"function":"Transcriptional activator; DNA-binding protein that specifically recognize the sequence 5'-YAAC[GT]G-3'. Plays an important role in the control of proliferation and differentiation of hematopoietic progenitor cells","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P10242/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYB","classification":"Not Classified","n_dependent_lines":228,"n_total_lines":1208,"dependency_fraction":0.18874172185430463},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYB","total_profiled":1310},"omim":[{"mim_id":"621288","title":"LIN52 DREAM MUVB CORE COMPLEX COMPONENT; LIN52","url":"https://www.omim.org/entry/621288"},{"mim_id":"621287","title":"LIN37 DREAM MUVB CORE COMPLEX COMPONENT; LIN37","url":"https://www.omim.org/entry/621287"},{"mim_id":"620986","title":"T-SNARE DOMAIN-CONTAINING PROTEIN 1; TSNARE1","url":"https://www.omim.org/entry/620986"},{"mim_id":"618139","title":"MIS18-BINDING PROTEIN 1; MIS18BP1","url":"https://www.omim.org/entry/618139"},{"mim_id":"618116","title":"BONE MARROW FAILURE SYNDROME 4; BMFS4","url":"https://www.omim.org/entry/618116"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":33.1},{"tissue":"breast","ntpm":18.9},{"tissue":"intestine","ntpm":24.9},{"tissue":"lymphoid tissue","ntpm":61.5}],"url":"https://www.proteinatlas.org/search/MYB"},"hgnc":{"alias_symbol":["c-myb"],"prev_symbol":[]},"alphafold":{"accession":"P10242","domains":[{"cath_id":"1.10.10.60","chopping":"44-88","consensus_level":"medium","plddt":93.2778,"start":44,"end":88},{"cath_id":"1.10.10.60","chopping":"92-140","consensus_level":"medium","plddt":95.8816,"start":92,"end":140},{"cath_id":"1.10.10.60","chopping":"143-197","consensus_level":"medium","plddt":93.4076,"start":143,"end":197}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10242","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10242-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10242-F1-predicted_aligned_error_v6.png","plddt_mean":58.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYB","jax_strain_url":"https://www.jax.org/strain/search?query=MYB"},"sequence":{"accession":"P10242","fasta_url":"https://rest.uniprot.org/uniprotkb/P10242.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10242/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10242"}},"corpus_meta":[{"pmid":"1709592","id":"PMC_1709592","title":"A 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role of c-MYB in benzene-initiated toxicity.","date":"2005","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/15935814","citation_count":25,"is_preprint":false},{"pmid":"1405703","id":"PMC_1405703","title":"c-myc and c-myb expression in acute myelogenous leukemia.","date":"1992","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/1405703","citation_count":25,"is_preprint":false},{"pmid":"23838059","id":"PMC_23838059","title":"Gene delivery of c-myb increases bone formation surrounding oral implants.","date":"2013","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/23838059","citation_count":25,"is_preprint":false},{"pmid":"26661713","id":"PMC_26661713","title":"C-myb Regulates Autophagy for Pulp Vitality in Glucose Oxidative Stress.","date":"2015","source":"Journal of dental 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Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26768615","citation_count":24,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44483,"output_tokens":10720,"usd":0.147124,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21302,"output_tokens":5997,"usd":0.128218,"stage2_stop_reason":"end_turn"},"total_usd":0.275342,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"c-myb is required for definitive (adult-type) fetal liver hematopoiesis but not for primitive (yolk sac) erythropoiesis; homozygous c-myb knockout mice die by embryonic day 15 with severe anemia due to failure of adult-type hematopoietic progenitor cell proliferation in the fetal liver.\",\n      \"method\": \"Homologous recombination knockout in mouse embryonic stem cells; phenotypic analysis of homozygous mutant embryos\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined cellular phenotype, replicated across multiple lineages, foundational study\",\n      \"pmids\": [\"1709592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Constitutive expression of full-length human c-myb cDNA blocks DMSO-induced erythroid differentiation of Friend murine erythroleukemia cells, establishing a causal role for c-myb in inhibiting erythroid differentiation.\",\n      \"method\": \"Stable transfection of c-myb expression construct into F-MEL cells; differentiation assay with DMSO; methotrexate amplification of transgene\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in cell line with defined differentiation phenotype, single lab\",\n      \"pmids\": [\"2832742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CBP (CREB-binding protein) is a direct transcriptional coactivator of c-Myb; CBP binds the transactivation domain of c-Myb in a phosphorylation-independent manner in vitro, and a c-Myb/CBP complex forms in vivo (yeast two-hybrid). CBP stimulates c-Myb-dependent transcription, and adenovirus E1A (which binds CBP) inhibits c-Myb-induced transactivation.\",\n      \"method\": \"In vitro GST pulldown, yeast two-hybrid, transactivation reporter assays, antisense CBP inhibition, E1A competition assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vitro binding, two-hybrid, functional reporter assays), single lab with rigorous controls\",\n      \"pmids\": [\"8598284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Myb controls hematopoietic stem cell proliferation and differentiation through interaction with the transcriptional coactivator p300; a point mutation (M303V) in the c-Myb transactivation domain disrupts its interaction with p300, causing thrombocytosis, anemia, lymphopenia, absence of eosinophils, and a 10-fold increase in cycling HSCs.\",\n      \"method\": \"ENU mutagenesis screen; identification of M303V point mutation; co-immunoprecipitation of c-Myb/p300; transactivation assays; hematopoietic phenotyping; cell cycle analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined point mutation disrupting specific protein interaction linked to precise in vivo phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"15691758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Pim-1 kinase binds to p100 (a c-Myb transcriptional coactivator) via yeast two-hybrid, phosphorylates p100 in vitro, forms a stable complex with p100 in animal cells, and stimulates c-Myb transcriptional activity in a p100-dependent manner downstream of Ras signaling.\",\n      \"method\": \"Yeast two-hybrid screen; in vitro kinase assay; co-immunoprecipitation; transactivation reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid, in vitro phosphorylation, co-IP, and functional reporter assays in single study with multiple orthogonal methods\",\n      \"pmids\": [\"9809063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The EVES motif in the c-Myb C-terminus mediates intramolecular interaction with the N-terminal DNA-binding domain (via yeast two-hybrid), and also interacts intermolecularly with p100 coactivator. The EVES motif contains a phosphorylation site implicated in negative regulation of c-Myb activity.\",\n      \"method\": \"Yeast two-hybrid assay; domain mapping; identification of EVES motif; functional coactivation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus functional assays, single lab\",\n      \"pmids\": [\"8756344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"c-Myb, C/EBPalpha, and PU.1 cooperate to activate the neutrophil elastase (NE) promoter through binding to their respective cis elements; cooperative activation is mediated via DNA-binding sites and likely involves a coactivator protein, as synergistic DNA binding between the factors could not be demonstrated in gel shift assays.\",\n      \"method\": \"Transient transfection reporter assays; gel shift (EMSA); mutational analysis of promoter elements; cell-line-specific assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell lines, functional mutagenesis, single lab\",\n      \"pmids\": [\"8756629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structures of c-Myb DBD and C/EBPbeta DBD bound to promoter DNA revealed that C/EBPbeta interacts with R2 of c-Myb bound to a separate DNA fragment, with intervening DNA looping; point mutations in v-Myb R2 eliminate this interaction. GST pulldown and AFM confirmed long-range protein-protein interaction and DNA looping.\",\n      \"method\": \"X-ray crystallography; GST pulldown; luciferase transactivation assay; atomic force microscopy\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus multiple orthogonal biochemical validations (GST pulldown, AFM, functional assays)\",\n      \"pmids\": [\"11792321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Wnt-1 signal induces phosphorylation and proteasome-dependent degradation of c-Myb via the TAK1–HIPK2–NLK kinase cascade; NLK binds directly to c-Myb together with HIPK2, leading to c-Myb phosphorylation at multiple sites, followed by ubiquitination and degradation. Overexpression of NLK in M1 cells abrogates c-Myb's ability to maintain the undifferentiated state.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assays; proteasome inhibitor experiments; ubiquitination assays; M1 cell differentiation assay; overexpression studies\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, in vitro kinase, ubiquitination, functional differentiation assay) in single rigorous study\",\n      \"pmids\": [\"15082531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"p300 acetylates c-Myb at three lysine residues (K471, K480, K485) in the carboxyl-terminal conserved domain both in vitro and in vivo; acetylation dramatically increases c-Myb DNA binding activity and transactivation of mim-1 and CD34 promoters. The bromodomain of p300 is required for effective acetylation of c-Myb.\",\n      \"method\": \"In vitro acetyltransferase assay; in vivo acetylation detection; EMSA; luciferase reporter assay; site-directed mutagenesis (KA mutant)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro and in vivo acetylation demonstrated, mutagenesis of specific sites, functional consequences measured with multiple assays\",\n      \"pmids\": [\"10656693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CBP acetylates c-Myb at K438 and K441 within its negative regulatory domain (NRD) in vitro, and in vivo at those and additional p300-induced sites; acetylation of these sites enhances c-Myb's association with CBP and synergistically increases c-Myb transactivation activity. The C/H2 domain of CBP directly interacts with the NRD of c-Myb.\",\n      \"method\": \"In vitro acetyltransferase assay; site-directed mutagenesis; transactivation reporter assays; co-immunoprecipitation; domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzyme assay, site-specific mutagenesis, in vivo validation, functional assays\",\n      \"pmids\": [\"11073948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"The human c-myb gene product localizes to the nucleus and is associated with the nuclear matrix in leukemic cells.\",\n      \"method\": \"Immunostaining with antiserum generated against recombinant c-myb carboxyl-terminal protein; nuclear fractionation\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization by immunostaining, replicated across multiple samples\",\n      \"pmids\": [\"3014652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"c-myb protein degradation is energy-dependent, does not involve lysosomes or ubiquitin, and does not produce cleavage intermediates; heat shock increases c-myb protein half-life ~2-fold and reduces c-myb protein synthesis ~4-fold, with recovery being energy-dependent.\",\n      \"method\": \"Pulse-chase metabolic labeling; inhibitor studies (lysosomal, energy, ubiquitin); heat shock experiments; protein synthesis measurement\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic inhibitor studies and pulse-chase, single lab\",\n      \"pmids\": [\"3043180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"c-myb transactivates the human cdc2 gene promoter through two closely spaced Myb binding sites at -410 to -392 upstream of the transcription start site; mutations in the Myb binding sites abrogate c-myb-dependent CAT reporter activation.\",\n      \"method\": \"CAT reporter cotransfection; mutational analysis of Myb binding sites; electrophoretic mobility shift assay with bacterially expressed Myb protein\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis of promoter, EMSA, functional reporter, single lab\",\n      \"pmids\": [\"8420994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Truncation of either the amino or carboxyl terminus of c-Myb is sufficient for transformation of chicken bone marrow cells; full-length c-Myb overexpression does not transform. The normal N- and C-termini of c-Myb suppress transformation when fused to v-Myb.\",\n      \"method\": \"Retroviral expression of truncated c-Myb constructs; transformation assay of primary chicken bone marrow cells; clonogenic assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic domain truncation analysis with primary cell transformation assay, multiple constructs tested\",\n      \"pmids\": [\"2072904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Myb is recruited to the MLL histone methyltransferase complex through menin, contributing to MLL-mediated H3K4 methylation; silencing MYB in human leukemic cells causes global decrease in H3K4 methylation, decreased HOXA9 and MEIS1 expression, and reduced MLL and menin occupancy at the HOXA9 locus.\",\n      \"method\": \"Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); siRNA-mediated knockdown; methylation assays; H3K4me3 quantification\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, ChIP, and functional epistasis with multiple orthogonal methods\",\n      \"pmids\": [\"20093773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"c-Myb directly transactivates c-myc in a cell-lineage-dependent manner requiring direct DNA binding by Myb to Myb-binding sites in the c-myc promoter; de novo protein synthesis is not required for c-myc transactivation.\",\n      \"method\": \"Transient transfection reporter assays; S1 nuclease protection; mutational analysis; conditional c-Myb expression; cycloheximide inhibition\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell lines, promoter mutagenesis, conditional expression system, single lab\",\n      \"pmids\": [\"8474446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"c-Myb transactivates the CD34 promoter via specific Myb binding sites in the 5' flanking region; constitutive c-Myb expression induces endogenous CD34 mRNA and surface antigen in CD34-negative glioblastoma cells.\",\n      \"method\": \"CAT reporter transfection; EMSA; northern blot; c-Myb overexpression in fibroblasts and glioblastoma cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter-binding and functional reporter assays, induction of endogenous gene, single lab\",\n      \"pmids\": [\"7509358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"c-Maf physically associates with c-Myb and inhibits c-Myb-dependent transcription of the myeloid CD13/APN gene promoter; formation of inhibitory Myb-Maf complexes is developmentally regulated, highest in immature myeloid cells.\",\n      \"method\": \"Co-immunoprecipitation; reporter gene assays; western blot; developmental stage-specific cell line analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus functional reporter assays replicated across developmental stages\",\n      \"pmids\": [\"9566892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRAF7 binds to the DNA-binding domain of c-Myb via its WD40 repeats and stimulates c-Myb sumoylation at K523 and K499 (same sites as PIASy-induced sumoylation); sumoylated c-Myb is sequestered to the cytoplasm by TRAF7, inhibiting c-Myb transactivation activity.\",\n      \"method\": \"Co-immunoprecipitation; sumoylation assay; immunofluorescence localization; subcellular fractionation; transactivation reporter assays; site-directed mutagenesis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, defined sumoylation sites by mutagenesis, subcellular fractionation/localization, functional consequences all demonstrated\",\n      \"pmids\": [\"16162816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"c-Myb directly activates Gata3 transcription, and is required for upregulation of Gata3 in response to TCR signaling during positive selection; loss of c-Myb causes fewer helper T cells and gain-of-function c-Myb transgene blocks cytotoxic T cell development.\",\n      \"method\": \"Conditional c-Myb knockout and c-Myb transgenic mice; reporter gene assays demonstrating Gata3 as direct c-Myb target; flow cytometric analysis of T cell development\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic gain and loss of function plus direct target gene validation with reporter assays\",\n      \"pmids\": [\"17641686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-myb directly transactivates KLF1 and LMO2 promoters (demonstrated by ChIP and luciferase reporter assay) to support erythropoiesis; c-myb silencing in human CD34+ cells shifts fate toward megakaryocyte at expense of erythroid lineage, and this defect is rescued by KLF1 or LMO2 overexpression.\",\n      \"method\": \"siRNA knockdown; chromatin immunoprecipitation; luciferase reporter assay; retroviral rescue experiments; clonogenic assay; flow cytometry\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP + reporter assay + genetic rescue with multiple orthogonal methods\",\n      \"pmids\": [\"20686118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"miR-150 controls B cell differentiation by targeting c-Myb in a dose-dependent manner; gain and loss of miR-150 show that its effect on lymphocyte development is mediated through c-Myb, with combined c-Myb conditional/partial ablation confirming the miR-150–c-Myb epistasis.\",\n      \"method\": \"miR-150 loss-of-function (knockout) and gain-of-function (transgenic) mouse models; conditional c-Myb ablation; flow cytometric analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic manipulation of both miR and target in vivo, confirmed epistasis\",\n      \"pmids\": [\"17923094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"c-Myb acts as a transcriptional activator of Tcf7 (Tcf1) to enhance CD8+ T cell memory development and as a repressor of Zeb2 to inhibit effector differentiation; the transactivation domain is necessary for restraining differentiation while the negative regulatory domain is critical for cell survival.\",\n      \"method\": \"Conditional c-Myb knockout; c-Myb overexpression; domain mutagenesis experiments; adoptive transfer; viral infection models; gene expression analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis plus KO and overexpression with defined molecular targets, multiple orthogonal methods\",\n      \"pmids\": [\"30778251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Myb promotes survival of CD4+CD8+ double-positive thymocytes by upregulating Bcl-xL; conditional deletion causes premature apoptosis of small preselection DP thymocytes independently of TCR signaling, and forced Bcl-xL expression rescues survival while c-Myb re-expression restores both Bcl-xL expression and the DP compartment.\",\n      \"method\": \"Conditional c-Myb knockout; Bcl-xL retroviral rescue; c-Myb retroviral rescue; apoptosis assays; Tcra repertoire analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue with both Bcl-xL and c-Myb, multiple orthogonal validations\",\n      \"pmids\": [\"20142358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"c-Myb is required for early T cell development; deletion of c-Myb causes a complete block just before the oligopotent thymocyte matures into the definitive T cell precursor.\",\n      \"method\": \"Homozygous null c-Myb/Rag1 chimeric mice; flow cytometric analysis of thymocyte populations\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic chimeric mouse model with defined developmental block\",\n      \"pmids\": [\"10323859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Myb is required for B cell development at the pro-B to pre-B cell transition; loss of c-Myb prevents normal B cell homeostasis by decreasing splenic B cell survival, associated with hyporesponsiveness to BLyS, decreased BR3 expression, and altered PKCdelta nuclear accumulation.\",\n      \"method\": \"Tissue-specific (conditional) Myb inactivation; flow cytometry; survival assays; BLyS receptor expression analysis; PKCdelta localization studies\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined molecular pathway components, multiple orthogonal methods\",\n      \"pmids\": [\"16169500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"c-Myb is absolutely required for differentiation of CD19+ B-lineage cells, controlling intrinsic survival and proper expression of IL-7 receptor alpha (CD127) and Ebf1; survival of c-Myb-deficient pro-B cells cannot be rescued by CD127 retroviral transduction, but B cell differentiation can be partially rescued by exogenous Ebf1.\",\n      \"method\": \"Tissue-specific Myb inactivation (Mb1-cre); retroviral rescue experiments; stromal cell culture; flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, rescue experiments distinguishing CD127-dependent and -independent pathways\",\n      \"pmids\": [\"19843942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"c-Myb and Pax-5 cooperatively bind to and activate the RAG-2 promoter in immature B cells through synergistic DNA binding; the C-terminus of c-Myb mediates physical interaction with Pax-5, and dominant-negative c-Myb suppresses RAG-2 promoter activity.\",\n      \"method\": \"Reporter gene assays; EMSA; co-immunoprecipitation; dominant-negative mutant experiments; deletion analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA, co-IP, functional reporter with dominant-negative, single lab\",\n      \"pmids\": [\"11781241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Casein kinase II (CKII) phosphorylates c-Myb at Ser-11 and Ser-12; replacing these serines with alanine increases DNA-binding affinity (up to 10-fold reduced dissociation constant) and increases transactivation activity on mim-1 and synthetic promoters.\",\n      \"method\": \"In vitro kinase assay; site-directed mutagenesis; EMSA with dissociation constant measurement; transactivation reporter assays\",\n      \"journal\": \"Cellular & molecular biology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus mutagenesis and functional assays, single lab\",\n      \"pmids\": [\"7735324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"p42mapk (ERK2) phosphorylates avian and murine c-Myb but not AMV v-Myb in vitro on serine and threonine residues mapping to the C-terminal negative regulatory domain.\",\n      \"method\": \"In vitro kinase assay with bacterially expressed Myb proteins; phosphoamino acid analysis; deletion mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay with domain mapping, single lab\",\n      \"pmids\": [\"8336948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Phosphorylation of c-Myb by Ser/Thr kinases (inhibited by okadaic acid) leads to hyperphosphorylation causing conformational changes and extremely rapid proteasome-dependent degradation; Ser/Thr phosphatases normally prevent the conformational changes that target c-Myb for degradation. The hyperphosphorylated form retains DNA binding activity.\",\n      \"method\": \"Okadaic acid phosphatase inhibitor treatment; pulse-chase protein stability assay; proteasome inhibitor; EMSA; phosphoamino acid analysis; antibody conformational recognition assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical inhibitor studies with pulse-chase and EMSA, single lab\",\n      \"pmids\": [\"10851088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mebendazole induces c-MYB protein degradation via the proteasome by interfering with the HSP70 chaperone system, inhibiting AML colony formation in vitro and AML progression in mouse xenotransplantation in vivo.\",\n      \"method\": \"Proteasome inhibitor rescue experiments; HSP70 inhibition assays; colony formation assay; mouse xenotransplantation; gene expression signature analysis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic studies with proteasome/HSP70 inhibitors plus functional colony assay and in vivo model, single lab\",\n      \"pmids\": [\"29089643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Withaferin A (WFA) induces rapid c-MYB protein ablation by disrupting HSP70/HSC70 chaperone protein homeostasis via proteotoxicity and the unfolded protein response; anti-AML activity of WFA depends on c-MYB modulation and can be partially reversed by a stabilized c-MYB mutant.\",\n      \"method\": \"Proteasome inhibitor rescue; stabilized c-MYB mutant rescue; western blot; colony formation assay; disease progression assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic rescue with stabilized mutant plus chaperone pathway dissection, single lab\",\n      \"pmids\": [\"35368048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pin1 physically interacts with c-Myb in a phosphorylation-dependent manner at S528 (within the EVES motif), and this interaction increases c-Myb transactivation activity in a manner dependent on Pin1 catalytic activity; Pin1 interaction does not increase c-Myb DNA binding.\",\n      \"method\": \"Co-immunoprecipitation; site-directed mutagenesis; transactivation reporter assays; DNA-binding assays; mass spectrometry confirming S528 phosphorylation in vivo\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP in physiological cell line, site-specific mutagenesis, in vivo phosphorylation by MS, functional assays\",\n      \"pmids\": [\"18359295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"c-Myb and GATA-1 mutually inhibit each other's transcriptional activity through competitive binding to CBP; c-Myb, GATA-1, and CBP can form bipartite complexes but not a tripartite complex, with exclusive CBP binding being the molecular basis for mutual inhibition.\",\n      \"method\": \"Co-immunoprecipitation; transactivation reporter assays; domain mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus reporter assays, single lab, multiple pairwise interactions tested\",\n      \"pmids\": [\"10644988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-myb loss-of-function (missense I181N in the DNA recognition helix of repeat 3) in zebrafish abolishes definitive hematopoiesis while leaving primitive hematopoiesis intact, confirming evolutionary conservation of c-myb's essential role in definitive hematopoiesis across vertebrates.\",\n      \"method\": \"ENU mutagenesis; identification of c-myb(t25127) missense allele; zebrafish phenotypic analysis; genetic complementation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function allele with specific domain-disrupting mutation, confirms mechanistic conservation\",\n      \"pmids\": [\"20823231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"c-Myb-null embryonic stem cells fail to produce embryoid bodies with spontaneously contracting smooth muscle cells; mesodermal differentiation is unaffected but myocardin upregulation and SMC-specific gene expression (smooth muscle alpha-actin, SM22alpha, SMMHC) are impaired; c-myb-/- cells show reduced contribution to SMC lineage in chimeric embryos and aortas.\",\n      \"method\": \"c-myb-/- ES cell differentiation to embryoid bodies; RT-PCR; flow cytometry; chimeric embryo analysis; aorta chimerism assessment\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined molecular (myocardin) and cellular (SMC differentiation) phenotype, in vitro and in vivo\",\n      \"pmids\": [\"18187733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"c-Myb is required for normal progenitor cell homeostasis in colonic crypts; hypomorphic c-myb mutations targeting DNA binding, transactivation, or negative regulatory domains all reduce colonic crypt size through a progenitor proliferation defect mediated in part by reduced Cyclin E1 expression; tissue-specific adult colon deletion confirms requirement for crypt integrity and differentiation.\",\n      \"method\": \"Three distinct hypomorphic c-myb mouse strains; tissue-specific adult colon c-myb deletion; BrdU proliferation assay; cyclin E1 expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent alleles plus conditional deletion, molecular target (Cyclin E1) identified\",\n      \"pmids\": [\"17360438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"c-Myb activates the miR-200 family (miR-200b, miR-200a, miR-429, miR-200c, miR-141) by binding to Myb binding sites in their promoter regions; when co-expressed with ZEB1, ZEB1 repression dominates over c-Myb activation; promoter methylation during TGF-β-induced EMT overrides c-Myb-dependent activation.\",\n      \"method\": \"Ectopic expression and gene silencing; luciferase reporter assay with Myb binding site mutations; ChIP; bisulfite sequencing\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay with site mutagenesis, single lab\",\n      \"pmids\": [\"24067373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Alternative splicing of human c-myb produces a family of transcripts (using alternate exons 8A, 9A, 9B, 10A, 13A, 14A) encoding c-Myb proteins with identical DNA binding domains but unique C-terminal domains; these variant proteins exhibit quantitative and qualitative differences in transcriptional activities and specificities.\",\n      \"method\": \"Quantitative RT-PCR; polysome association assay; transactivation reporter assays; expression analysis in human leukemia samples\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with defined splice variants, single lab\",\n      \"pmids\": [\"18195038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"c-Myb represses T-bet expression in mature B cells to limit aberrant IgG2c/CXCR3/plasma cell differentiation during germinal center responses; deletion of c-Myb increases T-bet expression and results in aberrant plasma cell differentiation within the germinal center mediated by CXCR3.\",\n      \"method\": \"Conditional c-Myb deletion in mature B cells; flow cytometry; serum Ig quantification; gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic deletion with defined molecular pathway, single lab\",\n      \"pmids\": [\"28423310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"c-Myb is required for plasma cell migration to bone marrow; in the absence of c-Myb, c-Myb-deficient plasma cells fail to migrate along a CXCL12 gradient, resulting in absence of IgG+ antigen-specific plasma cells in bone marrow after immunization or infection.\",\n      \"method\": \"Conditional c-Myb deletion; in vitro migration assay to CXCL12; immunization and viral infection models; flow cytometry\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined molecular mechanism (CXCL12 chemokine response), in vitro migration assay, in vivo confirmation\",\n      \"pmids\": [\"26077717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"c-Myb binds the Bmi1 promoter and activates its transcription; c-Myb and Bmi1 are required for p190BCR/ABL-dependent B-cell leukemogenesis, and ectopic Bmi1 expression can partially rescue the proliferative defect caused by c-Myb loss.\",\n      \"method\": \"Co-immunoprecipitation; ChIP; luciferase reporter assay; knockdown; retroviral rescue; in vivo leukemia model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay for direct target, genetic rescue experiments, single lab\",\n      \"pmids\": [\"21960247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"c-Myb functions as a pioneer transcription factor; each repeat of the c-Myb DNA-binding domain binds histones, and the D152V mutation in repeat 3 disrupts histone binding, impairs chromatin opening (ATAC-seq), and abrogates c-Myb's ability to regulate differentiation-associated genes.\",\n      \"method\": \"ATAC-seq; histone binding assay; site-directed mutagenesis (D152V); transcriptome analysis; chromatin accessibility assay in K562 cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide chromatin accessibility assay (ATAC-seq) plus biochemical histone binding and mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"28472346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"An intact c-Myb binding site in the TCR-delta intronic enhancer (Edelta) is necessary for efficient VDJ recombination at the TCR-delta locus in vivo; transgenic minilocus recombination substrate with mutated Myb binding site in Edelta shows markedly reduced rearrangement.\",\n      \"method\": \"Transgenic mouse minilocus recombination substrate; mutation of Myb binding site in Edelta; PCR analysis of VDJ rearrangements\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic experiment with site-specific mutagenesis and direct measurement of recombination\",\n      \"pmids\": [\"8551234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Phosphorylation of c-Myb at Ser-11 and Ser-12 positively modulates DNA binding by overcoming the negative regulatory influence of the leucine zipper (LZ); LZ mutation or phosphorylation both enhance DNA binding activity, and phosphatase treatment reduces DNA binding of insect-cell-expressed c-Myb.\",\n      \"method\": \"In vitro binding assays with E. coli-expressed c-Myb proteins; CKII and PKA kinase assays; phosphatase treatment; insect cell expression; site-directed mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phosphorylation and binding assays with multiple expression systems, single lab\",\n      \"pmids\": [\"7478531\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"c-Myb is a nuclear sequence-specific transcription factor (recognizing C/T-AAC-G/T-G) that functions as an essential regulator of definitive hematopoiesis and multiple immune cell lineages; its transcriptional activity is controlled by a network of post-translational modifications (phosphorylation by CKII, p42mapk, and the TAK1–HIPK2–NLK cascade; acetylation by p300 and CBP at defined lysines; sumoylation by TRAF7/PIASy targeting to the cytoplasm; proteasome-dependent degradation triggered by hyperphosphorylation), by intramolecular interactions between its EVES-containing negative regulatory domain and its N-terminal DNA-binding domain, and by direct binding of coactivators (CBP, p300, p100) and repressors (GATA-1, c-Maf, ZEB); it acts as a pioneer transcription factor whose DBD binds histones and opens chromatin at target loci including cdc2, CD34, KLF1, LMO2, Bcl-xL, Gata3, Bmi1, and miR-200 family members, and its activity is regulated post-transcriptionally by miR-150 and miR-126 that target its 3'UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"c-Myb is a nuclear, nuclear-matrix-associated sequence-specific transcription factor that serves as a master regulator of definitive hematopoiesis: genetic ablation in mice abolishes adult-type fetal liver hematopoiesis while sparing primitive yolk-sac erythropoiesis [#0, #11], a requirement conserved to zebrafish where a DNA-recognition-helix mutation in repeat 3 selectively eliminates definitive blood [#36]. Its DNA-binding domain functions as a pioneer factor whose repeats bind histones and open chromatin, an activity destroyed by the D152V mutation in repeat 3 [#44]. Through direct binding to Myb sites, c-Myb activates a broad differentiation-associated target program including cdc2, c-myc, CD34, KLF1, LMO2, Bmi1, Gata3, Tcf7, and the miR-200 family, and represses Zeb2 and T-bet [#13, #16, #17, #21, #43, #20, #23, #39, #41]; it balances erythroid versus megakaryocytic fate (via KLF1/LMO2) and stage-specific lymphoid programs, and supports thymocyte survival by inducing Bcl-xL [#21, #24]. c-Myb governs successive checkpoints across the immune system — early T-cell maturation, the pro-B to pre-B transition and B-lineage survival, RAG-2-dependent recombination, helper/cytotoxic T fate, CD8 memory, and CXCL12-dependent plasma cell homing to bone marrow [#25, #26, #27, #28, #45, #20, #23, #42] — and also controls colonic crypt progenitor proliferation and smooth-muscle differentiation, extending its role beyond blood [#38, #37]. Transcriptional output is set by coactivator recruitment: CBP and p300 bind the transactivation/negative regulatory domain and acetylate defined C-terminal lysines to boost DNA binding and activity, with the p300-interacting M303V mutation deranging HSC homeostasis [#2, #9, #10, #3]; c-Myb competes with GATA-1 for CBP and is antagonized by c-Maf and ZEB1 [#35, #18, #39]. c-Myb is integrated into chromatin machinery by joining the menin/MLL complex to promote H3K4 methylation at HOXA9 [#15]. Its abundance and activity are tuned by an intramolecular EVES-domain autoinhibition relieved by Pin1 and p100 [#5, #34, #4], by phosphorylation (CKII at Ser-11/12 enhancing DNA binding, the Wnt-driven TAK1–HIPK2–NLK cascade and hyperphosphorylation driving proteasomal degradation) [#29, #46, #8, #31], and by TRAF7-stimulated sumoylation that sequesters it to the cytoplasm [#19]; oncogenic activation requires N- or C-terminal truncation that removes these autoinhibitory controls [#14], and chaperone-disrupting drugs that destabilize c-Myb are anti-leukemic [#32, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Establishing that the c-myb product is a nuclear, matrix-associated protein placed it in the compartment where it could act transcriptionally.\",\n      \"evidence\": \"Immunostaining and nuclear fractionation in leukemic cells\",\n      \"pmids\": [\"3014652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define DNA-binding specificity or target genes\", \"Nuclear matrix association not linked to function\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Gain-of-function showed c-myb actively blocks differentiation, framing it as a differentiation-suppressing regulator rather than a passive marker.\",\n      \"evidence\": \"Constitutive c-myb expression in DMSO-treated Friend erythroleukemia cells\",\n      \"pmids\": [\"2832742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of differentiation block not defined\", \"Direct target genes not identified\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Characterizing c-myb protein turnover as energy-dependent and ubiquitin-independent opened the question of how its abundance is controlled.\",\n      \"evidence\": \"Pulse-chase with lysosomal/energy/ubiquitin inhibitors and heat shock\",\n      \"pmids\": [\"3043180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation pathway not molecularly identified\", \"Later work implicated proteasome, partly contradicting ubiquitin-independence\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Knockout and truncation analyses defined c-myb's essential physiological role in definitive hematopoiesis and revealed that its termini are autoinhibitory checkpoints whose removal causes transformation.\",\n      \"evidence\": \"Mouse c-myb knockout embryos; retroviral expression of truncated c-Myb in chicken bone marrow transformation assay\",\n      \"pmids\": [\"1709592\", \"2072904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct hematopoietic target genes not yet mapped\", \"Mechanism by which termini suppress transformation undefined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Identification of direct promoter targets (cdc2, c-myc, CD34) and CKII phosphorylation established c-Myb as a sequence-specific activator whose DNA binding is post-translationally tuned.\",\n      \"evidence\": \"Reporter assays with Myb-site mutagenesis, EMSA, in vitro CKII kinase assay\",\n      \"pmids\": [\"8420994\", \"8474446\", \"7509358\", \"7735324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo occupancy not demonstrated at this stage\", \"Physiological kinases acting on Ser-11/12 in cells unclear\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Discovery of CBP/p100 coactivation and the autoinhibitory EVES motif defined the dual control of c-Myb activity by coactivator recruitment and intramolecular folding, and showed combinatorial promoter activation with C/EBPalpha and PU.1.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, reporter and coactivation assays; cooperative neutrophil elastase promoter activation\",\n      \"pmids\": [\"8598284\", \"8756344\", \"8756629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EVES autoinhibition is relieved physiologically not yet known\", \"Synergistic DNA binding with C/EBPalpha/PU.1 not demonstrable in EMSA\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Pim-1 phosphorylation of p100 and c-Maf antagonism linked c-Myb activity to upstream Ras signaling and to lineage-specific repression.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro kinase, co-IP, reporter assays; c-Maf co-IP and CD13 promoter assays\",\n      \"pmids\": [\"9809063\", \"9566892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation target on c-Myb itself not shown for Pim-1\", \"Structural basis of Myb-Maf repression unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Conditional and chimeric genetics pinpointed c-Myb as required at a specific early T-cell maturation checkpoint, refining its hematopoietic role to discrete developmental transitions.\",\n      \"evidence\": \"c-Myb-null/Rag1 chimeric mice with flow cytometric staging\",\n      \"pmids\": [\"10323859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target genes controlling this transition not identified\", \"Cell-intrinsic vs niche contribution not fully separated\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Acetylation by p300/CBP at defined C-terminal lysines and competitive CBP sequestration by GATA-1 established acetylation and coactivator competition as quantitative tuners of c-Myb output, while phosphorylation-driven hyperphosphorylation linked activity to proteasomal turnover.\",\n      \"evidence\": \"In vitro/in vivo acetyltransferase assays with site mutants, EMSA, co-IP; okadaic acid and proteasome inhibitor pulse-chase\",\n      \"pmids\": [\"10656693\", \"11073948\", \"10644988\", \"10851088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of physiological degradation-triggering kinases not defined here\", \"Crosstalk between acetylation and phosphorylation undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Crystallography of the c-Myb DBD with C/EBPbeta and cooperative binding with Pax-5 revealed long-range protein-protein interactions and DNA looping as a mechanism for combinatorial target activation.\",\n      \"evidence\": \"X-ray crystallography, GST pulldown, AFM; EMSA, co-IP and reporter assays at the RAG-2 promoter\",\n      \"pmids\": [\"11792321\", \"11781241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo prevalence of DNA looping unknown\", \"Generalizability beyond these partners untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The Wnt-1/TAK1–HIPK2–NLK cascade was defined as a signaling route that phosphorylates and degrades c-Myb to permit differentiation, connecting developmental signaling to c-Myb stability.\",\n      \"evidence\": \"Co-IP, in vitro kinase, ubiquitination and proteasome assays, M1 differentiation\",\n      \"pmids\": [\"15082531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise phosphodegron residues not fully mapped\", \"E3 ligase mediating degradation not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"A p300-interaction-disrupting point mutation (M303V) and TRAF7-driven sumoylation tied specific molecular interfaces to HSC homeostasis and to cytoplasmic sequestration, while B-cell genetics defined the pro-B to pre-B requirement.\",\n      \"evidence\": \"ENU M303V allele with HSC phenotyping; TRAF7 co-IP, sumoylation, fractionation; conditional B-cell Myb inactivation\",\n      \"pmids\": [\"15691758\", \"16162816\", \"16169500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How sumoylation and acetylation are coordinated unclear\", \"Direct B-cell survival target genes not all identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Direct activation of Gata3 in T cells, miR-150 targeting of c-Myb in B cells, and the colonic crypt requirement extended c-Myb's regulatory logic to lineage specification, post-transcriptional control, and non-hematopoietic progenitors.\",\n      \"evidence\": \"Conditional KO/transgenic mice, reporter assays; miR-150 gain/loss with c-Myb epistasis; hypomorphic alleles and colon deletion with Cyclin E1 readout\",\n      \"pmids\": [\"17641686\", \"17923094\", \"17360438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full target networks downstream of Gata3/Cyclin E1 not mapped\", \"miR-150 regulation in other lineages incompletely defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Pin1 isomerization at the EVES motif, alternative C-terminal splicing, and the smooth-muscle differentiation requirement diversified the understanding of how c-Myb activity and specificity are generated.\",\n      \"evidence\": \"Co-IP/MS at S528 with reporter assays; RT-PCR and functional assays of splice variants; c-myb-/- ES cell SMC differentiation\",\n      \"pmids\": [\"18359295\", \"18195038\", \"18187733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of individual splice variants in vivo unclear\", \"Pin1-EVES axis link to degradation not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Integration into the menin/MLL complex and direct KLF1/LMO2 activation defined how c-Myb shapes chromatin state and erythroid-versus-megakaryocyte fate, while the zebrafish allele confirmed evolutionary conservation of its definitive-hematopoiesis role.\",\n      \"evidence\": \"Reciprocal co-IP, ChIP, knockdown with H3K4me readout; ChIP/reporter with KLF1/LMO2 rescue; zebrafish ENU missense allele; conditional thymocyte Bcl-xL rescue\",\n      \"pmids\": [\"20093773\", \"20686118\", \"20823231\", \"20142358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry/architecture of c-Myb within the MLL complex undefined\", \"Genome-wide co-occupancy with menin/MLL not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstration that the c-Myb DBD binds histones and opens chromatin defined it mechanistically as a pioneer factor, and chaperone-disrupting drugs revealed its therapeutic vulnerability in AML.\",\n      \"evidence\": \"ATAC-seq, histone binding, D152V mutagenesis in K562; mebendazole/HSP70 and miR-200 ChIP/reporter; T-bet repression in B cells\",\n      \"pmids\": [\"28472346\", \"29089643\", \"24067373\", \"28423310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide rules for pioneer-mode site selection incomplete\", \"Whether chaperone-dependent stability is leukemia-selective unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Domain-resolved genetics in CD8 T cells separated c-Myb's transactivation function (restraining effector differentiation via Tcf7/Zeb2) from its negative regulatory domain's survival function, and earlier work tied it to plasma cell homing and B-lineage survival programs.\",\n      \"evidence\": \"Conditional KO, overexpression, domain mutants, adoptive transfer and infection; CXCL12 migration assay; Ebf1/CD127 rescue in pro-B cells\",\n      \"pmids\": [\"30778251\", \"26077717\", \"19843942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the NRD promotes survival mechanistically undefined\", \"Direct survival target genes downstream of the NRD unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the layered post-translational code (phosphorylation, acetylation, sumoylation, isomerization), EVES autoinhibition, and pioneer chromatin engagement are integrated in real time to select context-specific target programs across lineages remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model linking modification state to genome-wide occupancy\", \"E3 ligase(s) and full phosphodegron for proteasomal turnover unidentified\", \"Quantitative contribution of splice variants to lineage-specific output unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [13, 16, 17, 20, 21, 39, 43]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [13, 16, 20, 21, 23, 39, 41, 44]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [7, 13, 17, 29, 44, 46]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [44]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13, 16, 17, 21, 39, 43]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 36, 37, 38]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [20, 22, 23, 24, 25, 26, 27, 28, 41, 42, 45]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [15, 44]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 9, 10, 19, 31, 32, 33]}\n    ],\n    \"complexes\": [\"menin/MLL histone methyltransferase complex\"],\n    \"partners\": [\"CREBBP\", \"EP300\", \"TRAF7\", \"GATA1\", \"MAF\", \"MEN1\", \"PIN1\", \"PAX5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}