{"gene":"MYBL1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1988,"finding":"Human MYBL1 (A-myb) cDNA was isolated and sequenced, revealing a predicted protein of ~745 amino acids with three conserved domains (I, II, III) homologous to the c-myb DNA-binding domain; mRNA was ~5.0 kb.","method":"cDNA library screening, sequence analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — foundational cloning paper establishing primary structure; no functional assay, but replicated across multiple studies","pmids":["3060855"],"is_preprint":false},{"year":1994,"finding":"Human A-MYB protein is a nuclear transcriptional activator ~90 kDa in size; it binds the classical c-myb recognition sequence PyAACG/TG (specifically preferring TAACGG over TAAGTG) and activates transcription 6–10-fold more strongly than c-myb in NIH3T3 cells. Transactivation requires both the DNA-binding domain and an acidic domain; DNA-binding requires the N-terminal three-repeat region.","method":"Reporter gene cotransfection, gel retardation assay, DNase I footprinting, Western blot, deletion mutagenesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro DNA-binding assays (footprint, gel shift), mutagenesis, and transactivation assays in multiple studies converge","pmids":["8058310"],"is_preprint":false},{"year":1994,"finding":"Mouse A-myb encodes a transcriptional activator with properties similar to c-myb and v-myb proteins; during embryogenesis it is expressed in proliferating neuronal precursor cells, and in adult mice it is expressed during early spermatogenesis and in germinal-center B lymphocytes.","method":"Reporter gene transactivation assays, Northern blot, in situ hybridization, chromosome mapping","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transactivation assay plus tissue localization by multiple methods in single lab","pmids":["7813437"],"is_preprint":false},{"year":1994,"finding":"Chicken A-myb encodes a transcriptional activator that transactivates myb-responsive reporter genes and activates myb-inducible endogenous genes when stably expressed in macrophage cell line; expressed in fibroblasts unlike c-myb.","method":"Reporter gene transactivation, stable expression in macrophage cell line, Northern blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transactivation assay plus endogenous gene activation, single lab","pmids":["8058311"],"is_preprint":false},{"year":1994,"finding":"Murine A-myb exhibits differential splicing producing alternatively spliced mRNAs encoding smaller proteins; expression is highest in type A spermatogonia and pachytene spermatocytes, with down-regulation upon terminal differentiation to mature spermatozoa.","method":"Northern blot, in situ hybridization, cDNA sequence analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (Northern, in situ), single lab, consistent with other studies","pmids":["8084617"],"is_preprint":false},{"year":1995,"finding":"Human A-Myb contains two negative regulatory domains in addition to a DNA-binding domain and a transactivation domain; these negative regulatory domains dampen transactivation activity, and A-Myb functions predominantly in testis and peripheral blood leukocytes.","method":"Deletion mutagenesis, reporter gene cotransfection","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mapping of functional domains by mutagenesis and reporter assays, single lab","pmids":["7821437"],"is_preprint":false},{"year":1997,"finding":"The transactivation domain of A-Myb maps to residues 218–319 (centred on a charged region 259–281); a region immediately downstream (320–482) inhibits DNA binding; the C-terminal ~110 residues (643–752) negatively regulate maximal transactivation. A-Myb physically interacts with the coactivator CBP (and its homologue p300) through the charged region, and CBP synergizes with A-Myb in a dose-dependent, E1A-inhibitable manner.","method":"Deletion mutagenesis, reporter gene cotransfection, co-immunoprecipitation / binding assay with CBP","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — functional domain mapping by mutagenesis combined with physical interaction data; findings on CBP/p300 coactivation later independently confirmed","pmids":["9210395"],"is_preprint":false},{"year":1997,"finding":"The C-terminal regulatory domain of A-Myb is phosphorylated by cyclin A– and cyclin E–associated kinases, which relieves C-terminal inhibition and increases transactivation potential; A-myb mRNA peaks at the late G1/early S-phase transition, suggesting A-Myb activity is controlled by two mechanisms (transcription and CDK phosphorylation) to peak at G1/S.","method":"In vitro kinase assay, reporter gene cotransfection with cyclin expression vectors, cell cycle synchronization, Northern blot","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphorylation combined with functional derepression assay, cell-cycle timing data, single rigorous study","pmids":["9285555"],"is_preprint":false},{"year":1997,"finding":"A-myb is expressed in bovine aortic smooth muscle cells in a cell cycle-dependent manner (peaks at late G1/S); it strongly transactivates MBS-containing reporters (~30-fold) and the c-myc promoter (~50-fold); co-microinjection of A-myb with c-myc synergistically drives quiescent SMCs into S phase, demonstrating cooperation with c-myc in cell cycle progression.","method":"Northern blot, nuclear run-on, reporter gene transfection, microinjection into quiescent cells with BrdU labeling","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (nuclear run-on, reporter assay, microinjection/BrdU) in single rigorous study","pmids":["9111313"],"is_preprint":false},{"year":1997,"finding":"Mice homozygous for a germline A-myb null mutation develop normally to term but display: (1) male infertility due to spermatogenic arrest at the pachytene stage of meiotic prophase, and (2) female breast epithelial underdevelopment with failure to nurse pups. These phenotypes establish essential roles for A-myb in spermatogenesis and mammary gland development.","method":"Gene targeting/knockout mouse, morphological and histological analysis of testes and mammary glands","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — germline knockout with specific, well-characterized phenotypic readouts; landmark paper replicated and extended by later studies","pmids":["9109487"],"is_preprint":false},{"year":1997,"finding":"A-Myb expression in human tonsillar B cells is restricted to the dark zone (centroblasts), is cell cycle-regulated (detectable only in S and G2/M phases, absent in G0/G1), and is not induced by diverse in vitro polyclonal activators that otherwise drive B-cell proliferation, indicating A-Myb marks a specific in vivo centroblast state rather than proliferation per se.","method":"In situ hybridization, FACS cell cycle analysis, in vitro stimulation experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in situ hybridization plus cell-cycle FACS, single lab, two orthogonal methods","pmids":["9510180"],"is_preprint":false},{"year":2000,"finding":"A-Myb up-regulates bcl-2 promoter activity in t(14;18) follicular lymphoma cells through a Cdx homeodomain protein binding site; A-Myb co-purifies with Cdx2 on the Cdx binding sequence, but direct Myb binding to this sequence could not be demonstrated; mutation of the Cdx site abolishes A-Myb-responsive up-regulation. Co-transfection of A-Myb and Cdx2 strongly synergizes in activating the bcl-2 P2 promoter.","method":"Promoter deletion analysis, UV cross-linking, co-immunoprecipitation with Cdx2, reporter gene assay, mutagenesis, Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (UV cross-linking, co-IP, mutagenesis) in single lab; direct A-Myb binding to site was not demonstrated (negative result noted)","pmids":["10692454"],"is_preprint":false},{"year":2004,"finding":"Vertebrate B-Myb but not A-Myb or c-Myb can complement loss of Drosophila Myb in hemocyte proliferation; A-Myb and c-Myb cause lethality in Drosophila, indicating A-Myb has acquired neomorphic functions distinct from the ancestral proliferative Myb function shared by B-Myb and Dm-Myb.","method":"Genetic complementation in Drosophila (transgenic rescue), hemocyte proliferation assay","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis/complementation, single lab, clear functional distinction between paralogs","pmids":["15489525"],"is_preprint":false},{"year":2005,"finding":"The Wnt-NLK signaling pathway inhibits A-Myb transcriptional activity by a mechanism distinct from c-Myb: NLK and HIPK2 bind directly to A-Myb and NLK phosphorylates A-Myb, but unlike c-Myb, A-Myb is not degraded. Instead, NLK phosphorylation disrupts the interaction between A-Myb and its coactivator CBP, blocking transactivation; furthermore, NLK induces methylation of histone H3 at lysine-9 at A-Myb-bound promoter regions.","method":"Co-immunoprecipitation, reporter gene assay, in vitro kinase assay, chromatin immunoprecipitation (ChIP) for H3K9 methylation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, in vitro kinase, reporter assay, ChIP) establishing pathway mechanism in single rigorous study","pmids":["16055500"],"is_preprint":false},{"year":2009,"finding":"RFX2 is a downstream target of A-MYB in pachytene spermatocytes: A-MYB binds MYB-binding sites in the Rfx2 promoter in vivo (ChIP), activates Rfx2 promoter in transfected cells, and Rfx2 expression is virtually eliminated in A-myb knockout testes. A-MYB expression is up-regulated specifically in pachytene spermatocytes, preceding RFX2 induction.","method":"Chromatin immunoprecipitation (ChIP), electrophoretic gel shift, co-transfection reporter assay, A-myb knockout analysis, immunohistology","journal":"BMC developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP, gel shift, reporter assay, and genetic loss-of-function converge on direct A-MYB→Rfx2 regulatory relationship","pmids":["20003220"],"is_preprint":false},{"year":2011,"finding":"MYBL1 is a male-specific master regulator of meiosis in spermatocytes: a separation-of-function allele (Mybl1repro9) causes defects in autosome synapsis at pachynema, unsynapsed sex chromosomes, incomplete DSB repair, and absence of crossovers. ChIP-chip and promoter bioinformatic analysis identified direct MYBL1 target genes involved in multiple meiotic processes including cell cycle progression through pachynema; MYBL1 protein appears specifically in pachynema.","method":"Genetic screen (ENU mutagenesis), histological/cytological analysis of meiosis, ChIP-chip, gene expression profiling, bioinformatic promoter analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, ChIP-chip, expression, cytology) establishing master regulatory role with direct target identification","pmids":["21750041"],"is_preprint":false},{"year":2013,"finding":"Truncated MYBL1 transcripts (lacking the C-terminal negative-regulatory domain), generated by 8q13.1 partial duplication in diffuse pediatric low-grade gliomas, induce anchorage-independent growth in 3T3 cells and tumor formation in nude mice, establishing oncogenic gain-of-function activity of C-terminally truncated MYBL1.","method":"Whole-genome sequencing, copy-number analysis, functional assay (anchorage-independent growth in 3T3 cells, nude mouse xenograft)","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional in vitro and in vivo oncogenic assays with truncated MYBL1 constructs; mechanistically defines role of C-terminal domain as negative regulator","pmids":["23633565"],"is_preprint":false},{"year":2015,"finding":"Novel t(8;9) and t(8;14) translocations fuse MYBL1 to NFIB and RAD51B, respectively, in adenoid cystic carcinoma (ACC) lacking MYB-NFIB. All MYBL1 alterations involve deletion of the C-terminal negative regulatory domain and correlate with high MYBL1 expression; MYB and MYBL1 translocations produce similar gene expression profiles, suggesting interchangeable oncogenic driver roles.","method":"RNA sequencing of archival FFPE samples, fusion transcript detection, gene expression profiling","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — RNA-seq-based fusion detection and expression profiling, replicated across multiple institutions","pmids":["26631070"],"is_preprint":false},{"year":2015,"finding":"Multiple MYBL1 rearrangements in ACC consistently involve deletion of the C-terminal negative regulatory domain and are associated with high MYBL1 expression; reciprocal and mutually exclusive expression of MYB and MYBL1 is a consistent feature; distinct gene expression profiles are associated with length of MYB/MYBL1 fusions, indicating biological importance of the C-terminal domain.","method":"Whole-genome sequencing, targeted molecular analysis, microarray gene-expression profiling, FISH","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — WGS plus expression profiling in validation cohort, single study, no functional rescue experiment","pmids":["26631609"],"is_preprint":false},{"year":2022,"finding":"MYBL1 binds directly to the ANGPT2 promoter and transcriptionally upregulates ANGPT2 mRNA, promoting tumor angiogenesis in hepatocellular carcinoma; PRMT5, MEP50, and WDR5 (histone post-translational modification factors) are required for MYBL1-mediated ANGPT2 upregulation. MYBL1-overexpressing HCC cells show increased sorafenib resistance reversed by anti-ANGPT2 antibody.","method":"Chromatin immunoprecipitation (ChIP), reporter gene assay, overexpression/knockdown functional assays (tube formation, HUVEC migration, CAM neovascularization, xenograft), Western blot, co-immunoprecipitation with PRMT5/MEP50/WDR5","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional assays in single lab; co-factor requirement based on Co-IP without full mechanistic reconstitution","pmids":["35987690"],"is_preprint":false},{"year":2023,"finding":"In mammalian meiosis, A-MYB (MYBL1) and BRDT cooperate to release paused RNA Polymerase II during late prophase I of spermatogenesis, orchestrating a ~3-fold transcriptional burst; A-MYB-dependent transcriptional activation is temporally segregated from meiotic recombination despite shared chromatin marks.","method":"ATAC-seq (chromatin accessibility), nascent transcription assay (GRO-seq or equivalent), processed mRNA sequencing, genome-wide Pol II occupancy mapping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genome-wide methods (chromatin accessibility, nascent transcription, mRNA-seq) in single rigorous study with mechanistic insight","pmids":["36990976"],"is_preprint":false}],"current_model":"MYBL1 (A-MYB) is a nuclear transcription factor that binds the consensus Myb recognition sequence (PyAACG/TG) via its N-terminal three-repeat DNA-binding domain and activates target gene transcription through an acidic transactivation domain (residues 218–319) that physically recruits the coactivator CBP/p300; its activity is positively regulated by cyclin A/E-dependent CDK phosphorylation of the C-terminal inhibitory domain and negatively regulated by the Wnt-NLK pathway (NLK phosphorylates A-MYB, disrupts CBP interaction, and promotes H3K9 methylation at target promoters); in spermatocytes A-MYB is an essential master regulator of pachytene-stage meiosis that—together with BRDT—orchestrates Pol II pause release and a major transcriptional burst, with direct targets including RFX2, and its loss causes pachytene arrest, failure of DSB repair, and loss of crossovers; deletion of its C-terminal negative-regulatory domain generates a constitutively active, oncogenic form responsible for recurrent fusions (MYBL1-NFIB, MYBL1-RAD51B, MYBL1-ACTN1) in adenoid cystic carcinoma and pediatric low-grade gliomas, and in hepatocellular carcinoma MYBL1 drives angiogenesis by directly transactivating ANGPT2 in a PRMT5/MEP50/WDR5-dependent manner."},"narrative":{"mechanistic_narrative":"MYBL1 (A-MYB) is a nuclear sequence-specific transcriptional activator that binds the classical Myb recognition element (PyAACG/TG, preferring TAACGG) through its N-terminal three-repeat DNA-binding domain and activates target transcription far more strongly than c-Myb [PMID:8058310]. Transactivation depends on an acidic activation domain mapping to residues 218–319, which physically recruits the coactivator CBP/p300; a downstream segment inhibits DNA binding and the C-terminal ~110 residues constitute a negative-regulatory domain that dampens maximal activity [PMID:9210395]. A-MYB activity is gated by the cell cycle and signaling: cyclin A/E–associated CDK phosphorylation of the C-terminal domain relieves its autoinhibition to peak activity at G1/S [PMID:9285555], while the Wnt-NLK pathway phosphorylates A-MYB to disrupt its CBP interaction and promote H3K9 methylation at bound promoters [PMID:16055500]. In male meiosis, A-MYB is an essential master regulator that appears specifically in pachytene spermatocytes and directs a program of meiotic genes—including the direct target RFX2—such that its loss causes pachytene arrest, defective synapsis, incomplete DSB repair, and absence of crossovers [PMID:9109487, PMID:20003220, PMID:21750041]; mechanistically it cooperates with BRDT to release paused RNA Pol II and drive a late-prophase transcriptional burst [PMID:36990976]. Deletion of the C-terminal negative-regulatory domain converts MYBL1 into a constitutively active oncogene: C-terminally truncated forms arising from duplication or recurrent fusions (MYBL1-NFIB, MYBL1-RAD51B) drive transformation in pediatric low-grade glioma and adenoid cystic carcinoma [PMID:23633565, PMID:26631070, PMID:26631609], and in hepatocellular carcinoma MYBL1 directly transactivates ANGPT2 to promote angiogenesis in a PRMT5/MEP50/WDR5-dependent manner [PMID:35987690].","teleology":[{"year":1988,"claim":"Establishing the primary structure of human A-myb identified it as a c-myb-related gene, raising the question of whether it functions as a transcription factor.","evidence":"cDNA library screening and sequence analysis revealing three conserved Myb-homology domains","pmids":["3060855"],"confidence":"Medium","gaps":["No functional or DNA-binding assay","Tissue and cell-cycle context unknown"]},{"year":1994,"claim":"Demonstrating that A-MYB is a nuclear activator binding the Myb consensus site answered whether the protein is functionally a transcription factor and showed it is a stronger activator than c-Myb.","evidence":"Gel retardation, DNase I footprinting, reporter cotransfection and deletion mutagenesis in NIH3T3 cells; orthologous activation assays in mouse and chicken with expression profiling","pmids":["8058310","7813437","8058311","8084617"],"confidence":"High","gaps":["Coactivators and partner proteins not identified","In vivo target genes unknown","Regulation of activity not defined"]},{"year":1995,"claim":"Mapping negative regulatory domains established that A-Myb activity is intrinsically autoinhibited, framing later work on how this restraint is relieved or lost.","evidence":"Deletion mutagenesis and reporter cotransfection","pmids":["7821437"],"confidence":"Medium","gaps":["Molecular signals controlling the negative domains unresolved","No structural detail"]},{"year":1997,"claim":"Defining the transactivation domain and its physical recruitment of CBP/p300, together with CDK-mediated relief of C-terminal autoinhibition, answered how A-Myb activates transcription and how its activity is timed to G1/S.","evidence":"Deletion mapping, CBP co-immunoprecipitation/binding, in vitro cyclin A/E kinase assays, cell-cycle synchronization; microinjection/BrdU cooperation with c-myc in smooth muscle cells","pmids":["9210395","9285555","9111313"],"confidence":"High","gaps":["Specific CDK responsible not pinpointed","Phosphosite-level mapping incomplete"]},{"year":1997,"claim":"Germline knockout established the physiological necessity of A-myb, revealing essential and non-redundant roles in pachytene-stage spermatogenesis and mammary development.","evidence":"Gene-targeted knockout mice with histological analysis of testes and mammary glands; B-cell and tissue expression profiling","pmids":["9109487","9510180"],"confidence":"High","gaps":["Direct meiotic target genes not yet identified","Mechanism of pachytene arrest unresolved"]},{"year":2000,"claim":"Identifying A-Myb cooperation with Cdx2 on the bcl-2 promoter probed how A-Myb can regulate genes beyond canonical Myb sites, via partner homeodomain factors.","evidence":"Promoter deletion, UV cross-linking, Cdx2 co-immunoprecipitation, mutagenesis and reporter assays in follicular lymphoma cells","pmids":["10692454"],"confidence":"Medium","gaps":["Direct A-Myb DNA binding to the Cdx site could not be demonstrated","Physiological relevance in B-cell biology unconfirmed"]},{"year":2005,"claim":"Showing that Wnt-NLK signaling inhibits A-Myb by disrupting CBP binding and inducing repressive H3K9 methylation answered how A-Myb is negatively regulated by extracellular signaling distinct from c-Myb degradation.","evidence":"Co-IP, in vitro kinase assay, reporter assays, and ChIP for H3K9 methylation","pmids":["16055500"],"confidence":"High","gaps":["NLK phosphosites on A-Myb not mapped","Histone methyltransferase recruited not identified"]},{"year":2011,"claim":"Genome-wide target mapping and a separation-of-function allele established MYBL1 as a male-specific master regulator of meiotic progression, defining direct targets including RFX2 and linking loss to synapsis, DSB repair and crossover failure.","evidence":"ENU separation-of-function allele, meiotic cytology, ChIP-chip and expression profiling; ChIP, gel shift, reporter and knockout validation of the Rfx2 target","pmids":["21750041","20003220"],"confidence":"High","gaps":["Full direct target network incompletely defined","Mechanism coupling transcription to recombination unresolved"]},{"year":2013,"claim":"Functional assays of C-terminally truncated MYBL1 established that loss of the negative-regulatory domain produces an oncogenic gain-of-function form, connecting domain architecture to tumorigenesis.","evidence":"Whole-genome sequencing of pediatric low-grade gliomas with anchorage-independent growth and nude-mouse xenograft assays of truncated constructs","pmids":["23633565"],"confidence":"High","gaps":["Downstream oncogenic target genes in glioma not defined","Mechanism of transformation beyond derepression unknown"]},{"year":2015,"claim":"Discovery of recurrent MYBL1-NFIB and MYBL1-RAD51B fusions in adenoid cystic carcinoma established MYBL1 as an interchangeable oncogenic driver with MYB, all alterations converging on C-terminal domain deletion.","evidence":"RNA-seq and whole-genome sequencing fusion detection plus expression profiling across cohorts","pmids":["26631070","26631609"],"confidence":"Medium","gaps":["No functional rescue of the specific fusions","Fusion partner contributions not dissected"]},{"year":2022,"claim":"Identifying ANGPT2 as a direct MYBL1 target dependent on PRMT5/MEP50/WDR5 revealed a pro-angiogenic transcriptional axis in hepatocellular carcinoma linked to sorafenib resistance.","evidence":"ChIP, reporter assays, overexpression/knockdown angiogenesis assays and xenografts, with co-IP of PRMT5/MEP50/WDR5","pmids":["35987690"],"confidence":"Medium","gaps":["Cofactor requirement rests on Co-IP without full reconstitution","Direct biochemical role of each cofactor undefined"]},{"year":2023,"claim":"Mapping A-MYB cooperation with BRDT in releasing paused Pol II answered how A-MYB drives the late-prophase transcriptional burst and showed transcription is temporally segregated from recombination.","evidence":"ATAC-seq, nascent transcription assays, mRNA-seq and genome-wide Pol II occupancy mapping in spermatocytes","pmids":["36990976"],"confidence":"High","gaps":["Direct A-MYB–BRDT physical interaction not detailed","How shared chromatin marks are temporally decoded unresolved"]},{"year":null,"claim":"How the same MYBL1 transcriptional output is differentially deployed across meiosis, B-cell/mammary development, and oncogenic contexts—and which cofactors and chromatin states specify each program—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Context-specific cofactor codes not defined","Structural basis of C-terminal autoinhibition unknown","Full direct target catalog across tissues incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,6,14,15,19]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,6,14,19]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[9,15,20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,17,19]}],"complexes":[],"partners":["CREBBP","EP300","NLK","HIPK2","CDX2","BRDT","PRMT5","WDR5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10243","full_name":"Myb-related protein A","aliases":["Myb-like protein 1"],"length_aa":752,"mass_kda":85.9,"function":"Transcription factor that specifically recognizes the sequence 5'-YAAC[GT]G-3' (PubMed:7987850, PubMed:8058310). Acts as a master regulator of male meiosis by promoting expression of piRNAs: activates expression of both piRNA precursor RNAs and expression of protein-coding genes involved in piRNA metabolism (By similarity). The piRNA metabolic process mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons, which is essential for the germline integrity (By similarity). Transcriptional activator of SOX30 (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P10243/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYBL1","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYBL1","total_profiled":1310},"omim":[{"mim_id":"604745","title":"TRANSCRIPTION FACTOR-LIKE 5; TCFL5","url":"https://www.omim.org/entry/604745"},{"mim_id":"601415","title":"MYB PROTOONCOGENE LIKE 2; MYBL2","url":"https://www.omim.org/entry/601415"},{"mim_id":"164035","title":"NUCLEOLIN; NCL","url":"https://www.omim.org/entry/164035"},{"mim_id":"159405","title":"MYB PROTOONCOGENE LIKE 1; MYBL1","url":"https://www.omim.org/entry/159405"},{"mim_id":"109565","title":"BCL6 TRANSCRIPTION REPRESSOR; BCL6","url":"https://www.omim.org/entry/109565"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":18.8},{"tissue":"testis","ntpm":11.0}],"url":"https://www.proteinatlas.org/search/MYBL1"},"hgnc":{"alias_symbol":["AMYB","A-myb"],"prev_symbol":[]},"alphafold":{"accession":"P10243","domains":[{"cath_id":"1.10.10.60","chopping":"34-84","consensus_level":"medium","plddt":91.3902,"start":34,"end":84},{"cath_id":"1.10.10.60","chopping":"90-136","consensus_level":"medium","plddt":96.3643,"start":90,"end":136},{"cath_id":"1.10.10.60","chopping":"141-194","consensus_level":"medium","plddt":93.7831,"start":141,"end":194}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10243","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10243-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10243-F1-predicted_aligned_error_v6.png","plddt_mean":57.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYBL1","jax_strain_url":"https://www.jax.org/strain/search?query=MYBL1"},"sequence":{"accession":"P10243","fasta_url":"https://rest.uniprot.org/uniprotkb/P10243.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10243/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10243"}},"corpus_meta":[{"pmid":"17012405","id":"PMC_17012405","title":"Light-induced 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1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8021494","citation_count":29,"is_preprint":false},{"pmid":"31481212","id":"PMC_31481212","title":"A non-LTR retrotransposon activates anthocyanin biosynthesis by regulating a MYB transcription factor in Capsicum annuum.","date":"2019","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/31481212","citation_count":28,"is_preprint":false},{"pmid":"34263934","id":"PMC_34263934","title":"SlPHL1, a MYB-CC transcription factor identified from tomato, positively regulates the phosphate starvation response.","date":"2021","source":"Physiologia plantarum","url":"https://pubmed.ncbi.nlm.nih.gov/34263934","citation_count":28,"is_preprint":false},{"pmid":"9111313","id":"PMC_9111313","title":"A-myb is expressed in bovine vascular smooth muscle cells during the late G1-to-S phase transition and cooperates with c-myc to mediate progression to S phase.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9111313","citation_count":28,"is_preprint":false},{"pmid":"9285555","id":"PMC_9285555","title":"Linking Myb to the cell cycle: cyclin-dependent phosphorylation and regulation of A-Myb activity.","date":"1997","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9285555","citation_count":27,"is_preprint":false},{"pmid":"37338208","id":"PMC_37338208","title":"A MYB activator, DcMYB11c, regulates carrot anthocyanins accumulation in petiole but not taproot.","date":"2023","source":"Plant, cell & environment","url":"https://pubmed.ncbi.nlm.nih.gov/37338208","citation_count":26,"is_preprint":false},{"pmid":"32680975","id":"PMC_32680975","title":"MORE FLORET1 Encodes a MYB Transcription Factor That Regulates Spikelet Development in Rice.","date":"2020","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32680975","citation_count":24,"is_preprint":false},{"pmid":"24400899","id":"PMC_24400899","title":"A MYB coiled-coil transcription factor interacts with NSP2 and is involved in nodulation in Lotus japonicus.","date":"2013","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/24400899","citation_count":24,"is_preprint":false},{"pmid":"26500265","id":"PMC_26500265","title":"Chicken gga-miR-181a targets MYBL1 and shows an inhibitory effect on proliferation of Marek's disease virus-transformed lymphoid cell line.","date":"2015","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/26500265","citation_count":24,"is_preprint":false},{"pmid":"32723808","id":"PMC_32723808","title":"MULTI-FLORET SPIKELET 2, a MYB Transcription Factor, Determines Spikelet Meristem Fate and Floral Organ Identity in Rice.","date":"2020","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32723808","citation_count":24,"is_preprint":false},{"pmid":"22878189","id":"PMC_22878189","title":"Contribution ratios of amyA, amyB, amyC genes to high-level α-amylase expression in Aspergillus oryzae.","date":"2012","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22878189","citation_count":23,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49631,"output_tokens":5370,"usd":0.114722,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13809,"output_tokens":4051,"usd":0.08516,"stage2_stop_reason":"end_turn"},"total_usd":0.199882,"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\": 1988,\n      \"finding\": \"Human MYBL1 (A-myb) cDNA was isolated and sequenced, revealing a predicted protein of ~745 amino acids with three conserved domains (I, II, III) homologous to the c-myb DNA-binding domain; mRNA was ~5.0 kb.\",\n      \"method\": \"cDNA library screening, sequence analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — foundational cloning paper establishing primary structure; no functional assay, but replicated across multiple studies\",\n      \"pmids\": [\"3060855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Human A-MYB protein is a nuclear transcriptional activator ~90 kDa in size; it binds the classical c-myb recognition sequence PyAACG/TG (specifically preferring TAACGG over TAAGTG) and activates transcription 6–10-fold more strongly than c-myb in NIH3T3 cells. Transactivation requires both the DNA-binding domain and an acidic domain; DNA-binding requires the N-terminal three-repeat region.\",\n      \"method\": \"Reporter gene cotransfection, gel retardation assay, DNase I footprinting, Western blot, deletion mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro DNA-binding assays (footprint, gel shift), mutagenesis, and transactivation assays in multiple studies converge\",\n      \"pmids\": [\"8058310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Mouse A-myb encodes a transcriptional activator with properties similar to c-myb and v-myb proteins; during embryogenesis it is expressed in proliferating neuronal precursor cells, and in adult mice it is expressed during early spermatogenesis and in germinal-center B lymphocytes.\",\n      \"method\": \"Reporter gene transactivation assays, Northern blot, in situ hybridization, chromosome mapping\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transactivation assay plus tissue localization by multiple methods in single lab\",\n      \"pmids\": [\"7813437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Chicken A-myb encodes a transcriptional activator that transactivates myb-responsive reporter genes and activates myb-inducible endogenous genes when stably expressed in macrophage cell line; expressed in fibroblasts unlike c-myb.\",\n      \"method\": \"Reporter gene transactivation, stable expression in macrophage cell line, Northern blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transactivation assay plus endogenous gene activation, single lab\",\n      \"pmids\": [\"8058311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Murine A-myb exhibits differential splicing producing alternatively spliced mRNAs encoding smaller proteins; expression is highest in type A spermatogonia and pachytene spermatocytes, with down-regulation upon terminal differentiation to mature spermatozoa.\",\n      \"method\": \"Northern blot, in situ hybridization, cDNA sequence analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (Northern, in situ), single lab, consistent with other studies\",\n      \"pmids\": [\"8084617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human A-Myb contains two negative regulatory domains in addition to a DNA-binding domain and a transactivation domain; these negative regulatory domains dampen transactivation activity, and A-Myb functions predominantly in testis and peripheral blood leukocytes.\",\n      \"method\": \"Deletion mutagenesis, reporter gene cotransfection\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mapping of functional domains by mutagenesis and reporter assays, single lab\",\n      \"pmids\": [\"7821437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The transactivation domain of A-Myb maps to residues 218–319 (centred on a charged region 259–281); a region immediately downstream (320–482) inhibits DNA binding; the C-terminal ~110 residues (643–752) negatively regulate maximal transactivation. A-Myb physically interacts with the coactivator CBP (and its homologue p300) through the charged region, and CBP synergizes with A-Myb in a dose-dependent, E1A-inhibitable manner.\",\n      \"method\": \"Deletion mutagenesis, reporter gene cotransfection, co-immunoprecipitation / binding assay with CBP\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — functional domain mapping by mutagenesis combined with physical interaction data; findings on CBP/p300 coactivation later independently confirmed\",\n      \"pmids\": [\"9210395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The C-terminal regulatory domain of A-Myb is phosphorylated by cyclin A– and cyclin E–associated kinases, which relieves C-terminal inhibition and increases transactivation potential; A-myb mRNA peaks at the late G1/early S-phase transition, suggesting A-Myb activity is controlled by two mechanisms (transcription and CDK phosphorylation) to peak at G1/S.\",\n      \"method\": \"In vitro kinase assay, reporter gene cotransfection with cyclin expression vectors, cell cycle synchronization, Northern blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphorylation combined with functional derepression assay, cell-cycle timing data, single rigorous study\",\n      \"pmids\": [\"9285555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A-myb is expressed in bovine aortic smooth muscle cells in a cell cycle-dependent manner (peaks at late G1/S); it strongly transactivates MBS-containing reporters (~30-fold) and the c-myc promoter (~50-fold); co-microinjection of A-myb with c-myc synergistically drives quiescent SMCs into S phase, demonstrating cooperation with c-myc in cell cycle progression.\",\n      \"method\": \"Northern blot, nuclear run-on, reporter gene transfection, microinjection into quiescent cells with BrdU labeling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (nuclear run-on, reporter assay, microinjection/BrdU) in single rigorous study\",\n      \"pmids\": [\"9111313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mice homozygous for a germline A-myb null mutation develop normally to term but display: (1) male infertility due to spermatogenic arrest at the pachytene stage of meiotic prophase, and (2) female breast epithelial underdevelopment with failure to nurse pups. These phenotypes establish essential roles for A-myb in spermatogenesis and mammary gland development.\",\n      \"method\": \"Gene targeting/knockout mouse, morphological and histological analysis of testes and mammary glands\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — germline knockout with specific, well-characterized phenotypic readouts; landmark paper replicated and extended by later studies\",\n      \"pmids\": [\"9109487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A-Myb expression in human tonsillar B cells is restricted to the dark zone (centroblasts), is cell cycle-regulated (detectable only in S and G2/M phases, absent in G0/G1), and is not induced by diverse in vitro polyclonal activators that otherwise drive B-cell proliferation, indicating A-Myb marks a specific in vivo centroblast state rather than proliferation per se.\",\n      \"method\": \"In situ hybridization, FACS cell cycle analysis, in vitro stimulation experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in situ hybridization plus cell-cycle FACS, single lab, two orthogonal methods\",\n      \"pmids\": [\"9510180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A-Myb up-regulates bcl-2 promoter activity in t(14;18) follicular lymphoma cells through a Cdx homeodomain protein binding site; A-Myb co-purifies with Cdx2 on the Cdx binding sequence, but direct Myb binding to this sequence could not be demonstrated; mutation of the Cdx site abolishes A-Myb-responsive up-regulation. Co-transfection of A-Myb and Cdx2 strongly synergizes in activating the bcl-2 P2 promoter.\",\n      \"method\": \"Promoter deletion analysis, UV cross-linking, co-immunoprecipitation with Cdx2, reporter gene assay, mutagenesis, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (UV cross-linking, co-IP, mutagenesis) in single lab; direct A-Myb binding to site was not demonstrated (negative result noted)\",\n      \"pmids\": [\"10692454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Vertebrate B-Myb but not A-Myb or c-Myb can complement loss of Drosophila Myb in hemocyte proliferation; A-Myb and c-Myb cause lethality in Drosophila, indicating A-Myb has acquired neomorphic functions distinct from the ancestral proliferative Myb function shared by B-Myb and Dm-Myb.\",\n      \"method\": \"Genetic complementation in Drosophila (transgenic rescue), hemocyte proliferation assay\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis/complementation, single lab, clear functional distinction between paralogs\",\n      \"pmids\": [\"15489525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The Wnt-NLK signaling pathway inhibits A-Myb transcriptional activity by a mechanism distinct from c-Myb: NLK and HIPK2 bind directly to A-Myb and NLK phosphorylates A-Myb, but unlike c-Myb, A-Myb is not degraded. Instead, NLK phosphorylation disrupts the interaction between A-Myb and its coactivator CBP, blocking transactivation; furthermore, NLK induces methylation of histone H3 at lysine-9 at A-Myb-bound promoter regions.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assay, in vitro kinase assay, chromatin immunoprecipitation (ChIP) for H3K9 methylation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, in vitro kinase, reporter assay, ChIP) establishing pathway mechanism in single rigorous study\",\n      \"pmids\": [\"16055500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RFX2 is a downstream target of A-MYB in pachytene spermatocytes: A-MYB binds MYB-binding sites in the Rfx2 promoter in vivo (ChIP), activates Rfx2 promoter in transfected cells, and Rfx2 expression is virtually eliminated in A-myb knockout testes. A-MYB expression is up-regulated specifically in pachytene spermatocytes, preceding RFX2 induction.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), electrophoretic gel shift, co-transfection reporter assay, A-myb knockout analysis, immunohistology\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP, gel shift, reporter assay, and genetic loss-of-function converge on direct A-MYB→Rfx2 regulatory relationship\",\n      \"pmids\": [\"20003220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MYBL1 is a male-specific master regulator of meiosis in spermatocytes: a separation-of-function allele (Mybl1repro9) causes defects in autosome synapsis at pachynema, unsynapsed sex chromosomes, incomplete DSB repair, and absence of crossovers. ChIP-chip and promoter bioinformatic analysis identified direct MYBL1 target genes involved in multiple meiotic processes including cell cycle progression through pachynema; MYBL1 protein appears specifically in pachynema.\",\n      \"method\": \"Genetic screen (ENU mutagenesis), histological/cytological analysis of meiosis, ChIP-chip, gene expression profiling, bioinformatic promoter analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, ChIP-chip, expression, cytology) establishing master regulatory role with direct target identification\",\n      \"pmids\": [\"21750041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Truncated MYBL1 transcripts (lacking the C-terminal negative-regulatory domain), generated by 8q13.1 partial duplication in diffuse pediatric low-grade gliomas, induce anchorage-independent growth in 3T3 cells and tumor formation in nude mice, establishing oncogenic gain-of-function activity of C-terminally truncated MYBL1.\",\n      \"method\": \"Whole-genome sequencing, copy-number analysis, functional assay (anchorage-independent growth in 3T3 cells, nude mouse xenograft)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional in vitro and in vivo oncogenic assays with truncated MYBL1 constructs; mechanistically defines role of C-terminal domain as negative regulator\",\n      \"pmids\": [\"23633565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Novel t(8;9) and t(8;14) translocations fuse MYBL1 to NFIB and RAD51B, respectively, in adenoid cystic carcinoma (ACC) lacking MYB-NFIB. All MYBL1 alterations involve deletion of the C-terminal negative regulatory domain and correlate with high MYBL1 expression; MYB and MYBL1 translocations produce similar gene expression profiles, suggesting interchangeable oncogenic driver roles.\",\n      \"method\": \"RNA sequencing of archival FFPE samples, fusion transcript detection, gene expression profiling\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — RNA-seq-based fusion detection and expression profiling, replicated across multiple institutions\",\n      \"pmids\": [\"26631070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Multiple MYBL1 rearrangements in ACC consistently involve deletion of the C-terminal negative regulatory domain and are associated with high MYBL1 expression; reciprocal and mutually exclusive expression of MYB and MYBL1 is a consistent feature; distinct gene expression profiles are associated with length of MYB/MYBL1 fusions, indicating biological importance of the C-terminal domain.\",\n      \"method\": \"Whole-genome sequencing, targeted molecular analysis, microarray gene-expression profiling, FISH\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — WGS plus expression profiling in validation cohort, single study, no functional rescue experiment\",\n      \"pmids\": [\"26631609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MYBL1 binds directly to the ANGPT2 promoter and transcriptionally upregulates ANGPT2 mRNA, promoting tumor angiogenesis in hepatocellular carcinoma; PRMT5, MEP50, and WDR5 (histone post-translational modification factors) are required for MYBL1-mediated ANGPT2 upregulation. MYBL1-overexpressing HCC cells show increased sorafenib resistance reversed by anti-ANGPT2 antibody.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), reporter gene assay, overexpression/knockdown functional assays (tube formation, HUVEC migration, CAM neovascularization, xenograft), Western blot, co-immunoprecipitation with PRMT5/MEP50/WDR5\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional assays in single lab; co-factor requirement based on Co-IP without full mechanistic reconstitution\",\n      \"pmids\": [\"35987690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In mammalian meiosis, A-MYB (MYBL1) and BRDT cooperate to release paused RNA Polymerase II during late prophase I of spermatogenesis, orchestrating a ~3-fold transcriptional burst; A-MYB-dependent transcriptional activation is temporally segregated from meiotic recombination despite shared chromatin marks.\",\n      \"method\": \"ATAC-seq (chromatin accessibility), nascent transcription assay (GRO-seq or equivalent), processed mRNA sequencing, genome-wide Pol II occupancy mapping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genome-wide methods (chromatin accessibility, nascent transcription, mRNA-seq) in single rigorous study with mechanistic insight\",\n      \"pmids\": [\"36990976\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYBL1 (A-MYB) is a nuclear transcription factor that binds the consensus Myb recognition sequence (PyAACG/TG) via its N-terminal three-repeat DNA-binding domain and activates target gene transcription through an acidic transactivation domain (residues 218–319) that physically recruits the coactivator CBP/p300; its activity is positively regulated by cyclin A/E-dependent CDK phosphorylation of the C-terminal inhibitory domain and negatively regulated by the Wnt-NLK pathway (NLK phosphorylates A-MYB, disrupts CBP interaction, and promotes H3K9 methylation at target promoters); in spermatocytes A-MYB is an essential master regulator of pachytene-stage meiosis that—together with BRDT—orchestrates Pol II pause release and a major transcriptional burst, with direct targets including RFX2, and its loss causes pachytene arrest, failure of DSB repair, and loss of crossovers; deletion of its C-terminal negative-regulatory domain generates a constitutively active, oncogenic form responsible for recurrent fusions (MYBL1-NFIB, MYBL1-RAD51B, MYBL1-ACTN1) in adenoid cystic carcinoma and pediatric low-grade gliomas, and in hepatocellular carcinoma MYBL1 drives angiogenesis by directly transactivating ANGPT2 in a PRMT5/MEP50/WDR5-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYBL1 (A-MYB) is a nuclear sequence-specific transcriptional activator that binds the classical Myb recognition element (PyAACG/TG, preferring TAACGG) through its N-terminal three-repeat DNA-binding domain and activates target transcription far more strongly than c-Myb [#1]. Transactivation depends on an acidic activation domain mapping to residues 218–319, which physically recruits the coactivator CBP/p300; a downstream segment inhibits DNA binding and the C-terminal ~110 residues constitute a negative-regulatory domain that dampens maximal activity [#6]. A-MYB activity is gated by the cell cycle and signaling: cyclin A/E–associated CDK phosphorylation of the C-terminal domain relieves its autoinhibition to peak activity at G1/S [#7], while the Wnt-NLK pathway phosphorylates A-MYB to disrupt its CBP interaction and promote H3K9 methylation at bound promoters [#13]. In male meiosis, A-MYB is an essential master regulator that appears specifically in pachytene spermatocytes and directs a program of meiotic genes—including the direct target RFX2—such that its loss causes pachytene arrest, defective synapsis, incomplete DSB repair, and absence of crossovers [#9, #14, #15]; mechanistically it cooperates with BRDT to release paused RNA Pol II and drive a late-prophase transcriptional burst [#20]. Deletion of the C-terminal negative-regulatory domain converts MYBL1 into a constitutively active oncogene: C-terminally truncated forms arising from duplication or recurrent fusions (MYBL1-NFIB, MYBL1-RAD51B) drive transformation in pediatric low-grade glioma and adenoid cystic carcinoma [#16, #17, #18], and in hepatocellular carcinoma MYBL1 directly transactivates ANGPT2 to promote angiogenesis in a PRMT5/MEP50/WDR5-dependent manner [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Establishing the primary structure of human A-myb identified it as a c-myb-related gene, raising the question of whether it functions as a transcription factor.\",\n      \"evidence\": \"cDNA library screening and sequence analysis revealing three conserved Myb-homology domains\",\n      \"pmids\": [\"3060855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or DNA-binding assay\", \"Tissue and cell-cycle context unknown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrating that A-MYB is a nuclear activator binding the Myb consensus site answered whether the protein is functionally a transcription factor and showed it is a stronger activator than c-Myb.\",\n      \"evidence\": \"Gel retardation, DNase I footprinting, reporter cotransfection and deletion mutagenesis in NIH3T3 cells; orthologous activation assays in mouse and chicken with expression profiling\",\n      \"pmids\": [\"8058310\", \"7813437\", \"8058311\", \"8084617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coactivators and partner proteins not identified\", \"In vivo target genes unknown\", \"Regulation of activity not defined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapping negative regulatory domains established that A-Myb activity is intrinsically autoinhibited, framing later work on how this restraint is relieved or lost.\",\n      \"evidence\": \"Deletion mutagenesis and reporter cotransfection\",\n      \"pmids\": [\"7821437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signals controlling the negative domains unresolved\", \"No structural detail\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defining the transactivation domain and its physical recruitment of CBP/p300, together with CDK-mediated relief of C-terminal autoinhibition, answered how A-Myb activates transcription and how its activity is timed to G1/S.\",\n      \"evidence\": \"Deletion mapping, CBP co-immunoprecipitation/binding, in vitro cyclin A/E kinase assays, cell-cycle synchronization; microinjection/BrdU cooperation with c-myc in smooth muscle cells\",\n      \"pmids\": [\"9210395\", \"9285555\", \"9111313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific CDK responsible not pinpointed\", \"Phosphosite-level mapping incomplete\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Germline knockout established the physiological necessity of A-myb, revealing essential and non-redundant roles in pachytene-stage spermatogenesis and mammary development.\",\n      \"evidence\": \"Gene-targeted knockout mice with histological analysis of testes and mammary glands; B-cell and tissue expression profiling\",\n      \"pmids\": [\"9109487\", \"9510180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct meiotic target genes not yet identified\", \"Mechanism of pachytene arrest unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying A-Myb cooperation with Cdx2 on the bcl-2 promoter probed how A-Myb can regulate genes beyond canonical Myb sites, via partner homeodomain factors.\",\n      \"evidence\": \"Promoter deletion, UV cross-linking, Cdx2 co-immunoprecipitation, mutagenesis and reporter assays in follicular lymphoma cells\",\n      \"pmids\": [\"10692454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct A-Myb DNA binding to the Cdx site could not be demonstrated\", \"Physiological relevance in B-cell biology unconfirmed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showing that Wnt-NLK signaling inhibits A-Myb by disrupting CBP binding and inducing repressive H3K9 methylation answered how A-Myb is negatively regulated by extracellular signaling distinct from c-Myb degradation.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, reporter assays, and ChIP for H3K9 methylation\",\n      \"pmids\": [\"16055500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NLK phosphosites on A-Myb not mapped\", \"Histone methyltransferase recruited not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genome-wide target mapping and a separation-of-function allele established MYBL1 as a male-specific master regulator of meiotic progression, defining direct targets including RFX2 and linking loss to synapsis, DSB repair and crossover failure.\",\n      \"evidence\": \"ENU separation-of-function allele, meiotic cytology, ChIP-chip and expression profiling; ChIP, gel shift, reporter and knockout validation of the Rfx2 target\",\n      \"pmids\": [\"21750041\", \"20003220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full direct target network incompletely defined\", \"Mechanism coupling transcription to recombination unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Functional assays of C-terminally truncated MYBL1 established that loss of the negative-regulatory domain produces an oncogenic gain-of-function form, connecting domain architecture to tumorigenesis.\",\n      \"evidence\": \"Whole-genome sequencing of pediatric low-grade gliomas with anchorage-independent growth and nude-mouse xenograft assays of truncated constructs\",\n      \"pmids\": [\"23633565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream oncogenic target genes in glioma not defined\", \"Mechanism of transformation beyond derepression unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery of recurrent MYBL1-NFIB and MYBL1-RAD51B fusions in adenoid cystic carcinoma established MYBL1 as an interchangeable oncogenic driver with MYB, all alterations converging on C-terminal domain deletion.\",\n      \"evidence\": \"RNA-seq and whole-genome sequencing fusion detection plus expression profiling across cohorts\",\n      \"pmids\": [\"26631070\", \"26631609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional rescue of the specific fusions\", \"Fusion partner contributions not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying ANGPT2 as a direct MYBL1 target dependent on PRMT5/MEP50/WDR5 revealed a pro-angiogenic transcriptional axis in hepatocellular carcinoma linked to sorafenib resistance.\",\n      \"evidence\": \"ChIP, reporter assays, overexpression/knockdown angiogenesis assays and xenografts, with co-IP of PRMT5/MEP50/WDR5\",\n      \"pmids\": [\"35987690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactor requirement rests on Co-IP without full reconstitution\", \"Direct biochemical role of each cofactor undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapping A-MYB cooperation with BRDT in releasing paused Pol II answered how A-MYB drives the late-prophase transcriptional burst and showed transcription is temporally segregated from recombination.\",\n      \"evidence\": \"ATAC-seq, nascent transcription assays, mRNA-seq and genome-wide Pol II occupancy mapping in spermatocytes\",\n      \"pmids\": [\"36990976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct A-MYB–BRDT physical interaction not detailed\", \"How shared chromatin marks are temporally decoded unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same MYBL1 transcriptional output is differentially deployed across meiosis, B-cell/mammary development, and oncogenic contexts—and which cofactors and chromatin states specify each program—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-specific cofactor codes not defined\", \"Structural basis of C-terminal autoinhibition unknown\", \"Full direct target catalog across tissues incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 6, 14, 15, 19]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 14]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 6, 14, 19]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [9, 15, 20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 17, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CREBBP\", \"EP300\", \"NLK\", \"HIPK2\", \"CDX2\", \"BRDT\", \"PRMT5\", \"WDR5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}