{"gene":"RBM15","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"RBM15 (OTT1) was identified as a novel gene encoding an RNA recognition motif (RRM)-containing protein with homology to Drosophila spen, fused to MKL1 in the t(1;22)(p13;q13) translocation of acute megakaryoblastic leukemia.","method":"Molecular cloning and sequencing of translocation breakpoints","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — original discovery of the gene and fusion by molecular cloning, replicated in multiple subsequent studies","pmids":["11431691"],"is_preprint":false},{"year":2002,"finding":"The OTT-MAL (RBM15-MKL1) fusion gene is present in all t(1;22) acute megakaryoblastic leukemia cases studied, with the translocation occurring via a non-homologous end joining mechanism involving a non-canonical topoisomerase II-like consensus sequence in the OTT gene.","method":"Nucleotide sequence analysis of translocation breakpoints, FISH, RT-PCR","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequence analysis of multiple breakpoints, single lab","pmids":["11746984"],"is_preprint":false},{"year":2005,"finding":"RBM15 (OTT1) interacts via its SPOC domain with the Epstein-Barr virus mRNA export factor EB2, and this interaction is mechanistically linked to splicing regulation; OTT1 and SHARP SPOC domains interact with SMRT/NCoR corepressors but with far weaker repressive activity than SHARP.","method":"Yeast two-hybrid screen, co-immunoprecipitation, transcriptional repression assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus co-IP, single lab, two orthogonal methods","pmids":["16129689"],"is_preprint":false},{"year":2007,"finding":"RBM15 modulates Notch-induced HES1 promoter activity in a cell-type-specific manner: it inhibits Notch-induced HES1 transcription in non-hematopoietic cells but stimulates it in hematopoietic cell lines. The N-terminus of RBM15 co-immunoprecipitates with RBPJkappa, a critical Notch signaling transcription factor.","method":"RNA interference, enforced expression, co-immunoprecipitation, luciferase reporter assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional assays with co-IP, single lab","pmids":["17283045"],"is_preprint":false},{"year":2007,"finding":"Conditional deletion of Ott1 (Rbm15) in adult mice causes a block in pro/pre-B differentiation leading to loss of peripheral B cells, myeloid and megakaryocytic expansion, and increased Lin-Sca-1+c-Kit+ hematopoietic stem cells, establishing Ott1 as required for B lymphopoiesis and inhibitory in myeloid/megakaryocytic lineages.","method":"Conditional knockout mouse model, flow cytometry, bone marrow analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular phenotypes across multiple hematopoietic lineages, rigorous in vivo model","pmids":["17376872"],"is_preprint":false},{"year":2008,"finding":"OTT (RBM15) interacts with histone deacetylase 3 (HDAC3), but this interaction is abolished in the OTT-BSAC fusion protein. OTT-BSAC, unlike BSAC alone, exclusively localizes to the nucleus (BSAC normally resides predominantly in cytoplasm), activating YY1-binding sequence-containing promoters.","method":"Co-immunoprecipitation, subcellular fractionation/localization, luciferase reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus localization plus functional reporter assays, single lab","pmids":["18667423"],"is_preprint":false},{"year":2008,"finding":"Germ-line deletion of Ott1 (Rbm15) causes embryonic lethality by E10.5 due to defects in placental vascular branching morphogenesis in spongiotrophoblast and syncytiotrophoblast layers. Trophoblast-specific rescue restores placenta and allows survival to term, revealing cardiac and splenic developmental abnormalities with enrichment of hypoxia-related gene expression changes.","method":"Germ-line and conditional knockout mouse models, conditional rescue with trophoblast-sparing Cre, global gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous genetic rescue experiment establishing tissue-specific requirement, multiple phenotypic readouts","pmids":["18981216"],"is_preprint":false},{"year":2009,"finding":"The OTT-MAL (RBM15-MKL1) fusion oncogene deregulates transcriptional activity of the Notch signaling pathway transcription factor RBPJ, causing abnormal fetal megakaryopoiesis; cooperation with activating MPL mutation efficiently induces short-latency AMKL in a knockin mouse model.","method":"Knockin mouse model, transcriptional reporter assays, genetic cooperation experiments with MPL mutation","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockin model with mechanistic transcription pathway analysis and genetic epistasis, replicated concept from Ma et al. 2007","pmids":["19287095"],"is_preprint":false},{"year":2009,"finding":"RBM15 binds specifically to the RNA helicase DBP5 and facilitates DBP5's direct contact with mRNA in vivo. RBM15 localizes to the nuclear envelope where it co-localizes with DBP5 and NXF1. Gene silencing of RBM15 leads to cytoplasmic depletion and nuclear accumulation of bulk mRNA and specific endogenous transcripts, establishing RBM15 as required for efficient mRNA nuclear export.","method":"Co-immunoprecipitation, RNA immunoprecipitation, siRNA knockdown, subcellular fractionation, immunofluorescence","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays plus functional knockdown with mRNA export phenotype, multiple orthogonal methods","pmids":["19786495"],"is_preprint":false},{"year":2010,"finding":"RBM15 and OTT3 (RBM15B) function as cellular NXF1 cofactors; knockdown of RBM15 leads to nuclear export deficiency of KSHV ORF57 RNA. KSHV ORF57 interacts directly with the RBM15 C-terminal SPOC domain to reduce RBM15 binding to ORF59 RNA.","method":"RNAi knockdown, RNA FISH, co-immunoprecipitation, subcellular RNA fractionation","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction mapping with SPOC domain plus functional knockdown phenotype, single lab","pmids":["21106733"],"is_preprint":false},{"year":2012,"finding":"RBM15 and the leukemogenic RBM15-MKL1 fusion protein directly interact with the Setd1b histone H3-Lys4 methyltransferase (KMT2G) via the RBM15 SPOC domain and the Setd1b LSD motif. Cytokine-independent proliferation of AMKL cells requires an intact RBM15 SPOC domain mediating this interaction.","method":"Co-immunoprecipitation, domain-mapping experiments, cytokine-independent growth assays with SPOC domain mutants","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction with domain mapping plus functional consequence, single lab","pmids":["22927943"],"is_preprint":false},{"year":2014,"finding":"Ott1 (Rbm15) controls alternative splicing of c-Mpl to generate a dominant-negative isoform (Mpl-TR) that inhibits HSC engraftment and attenuates Thpo signaling. Ott1 associates with Hdac3 and the histone methyltransferase Setd1b, binds both c-Mpl RNA and chromatin, and regulates H4 acetylation and H3K4me3 marks at the c-Mpl locus.","method":"Conditional KO mouse model, alternative splicing analysis, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), histone modification assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO, RIP, ChIP, splicing analysis) in single rigorous study establishing epigenetic mechanism","pmids":["25468569"],"is_preprint":false},{"year":2015,"finding":"RBM15 is methylated by PRMT1 at residue R578, which leads to its ubiquitin-mediated degradation via the E3 ligase CNOT4. RBM15 binds to pre-mRNA intronic regions of megakaryopoiesis-related genes (GATA1, RUNX1, TAL1, c-MPL) and recruits the splicing factor SF3B1 to the same intronic sites, regulating alternative splicing. PRMT1 overexpression blocks megakaryocyte differentiation by downregulating RBM15 protein; restoring RBM15 rescues differentiation.","method":"In vitro methylation assay, ubiquitylation assay, RNA immunoprecipitation (RIP), mass spectrometry, site-directed mutagenesis (R578), rescue experiments in AMKL cell lines","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assays with mutagenesis plus RIP and functional rescue, multiple orthogonal methods in one rigorous study","pmids":["26575292"],"is_preprint":false},{"year":2015,"finding":"A pooled shRNA screen identified RBM15 as required for Xist RNA-mediated silencing in X chromosome inactivation. RBM15 co-localizes with Xist RNA within the nuclear matrix subcompartment as shown by super-resolution 3D-SIM microscopy.","method":"shRNA screen, validation by knockdown, super-resolution 3D-SIM immunofluorescence microscopy, allelic RNA-seq","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — screen plus validation with direct localization evidence, single lab","pmids":["26190105"],"is_preprint":false},{"year":2016,"finding":"AS-RBM15, an antisense RNA transcribed from within exon 1 of RBM15, enhances RBM15 protein translation in a CAP-dependent manner. The region of AS-RBM15 overlapping with the 5'UTR of RBM15 is sufficient for upregulation of RBM15 protein translation.","method":"Overexpression and knockdown of AS-RBM15, translation reporter assays, domain mapping","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional domain mapping with CAP-dependent translation assays, single lab — NOTE: this paper is about the AS-RBM15 lncRNA regulating RBM15 protein; included because the mechanism directly establishes RBM15 protein level control","pmids":["27118388"],"is_preprint":false},{"year":2018,"finding":"Zc3h13/Flacc promotes m6A deposition by bridging the WTAP/Fl(2)d component of the m6A methyltransferase complex to the mRNA-binding factor Rbm15/Nito (Spenito), establishing RBM15 as the mRNA-binding adaptor that links target mRNAs to the METTL3 writer complex.","method":"Co-immunoprecipitation in Drosophila and mouse, m6A quantification, genetic analysis of sex determination pathway (epistasis), protein interaction mapping","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP across two species plus epistatic genetic analysis and functional m6A quantification, multi-lab relevant finding","pmids":["29535189"],"is_preprint":false},{"year":2019,"finding":"RBM15, as a subunit of the m6A methyltransferase complex, interacts with BAF155 mRNA and mediates its degradation through the mRNA methylation machinery in a METTL3-dependent manner. RBM15 ablation in neuronal cells and developing cortex increases BAF155 expression; RBM15 overexpression decreases BAF155 mRNA/protein and perturbs BAF155-dependent transcriptional activity and apical radial glial progenitor delamination.","method":"RIP assay, CRISPR/shRNA loss-of-function in vitro and in vivo, overexpression experiments, m6A pathway functional dependence on METTL3","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus in vivo CRISPR KO with defined phenotype and pathway epistasis (METTL3 dependence), single lab","pmids":["31020615"],"is_preprint":false},{"year":2020,"finding":"RBM15 binds to the Xist A-repeat region; deletion of the Xist A-repeat entirely abolishes m6A deposition in the Xist 5' m6A region without affecting exon VII m6A. In mESCs, RBM15 interacts with the m6A methyltransferase complex and with the SETD1B histone-modifying complex, plus several RNA metabolism proteins, as determined by epitope-tag purification and MS/MS.","method":"CRISPR/Cas9 deletion of Xist A-repeat, m6A-seq, allelic RNA-seq, epitope-tag purification followed by MS/MS interactome analysis","journal":"Wellcome open research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR mutagenesis with m6A-seq readout plus MS/MS interactome, multiple orthogonal methods establishing RBM15 recruitment to Xist 5' m6A region","pmids":["32258426"],"is_preprint":false},{"year":2020,"finding":"Loss of Rbm15 in zebrafish (cq96 mutant identified by forward genetic screen) causes a specific defect in liver maturation without affecting hepatoblast specification, differentiation, or hepatocyte proliferation/apoptosis. The mTORC1 pathway is hyperactivated in rbm15-deficient hepatocytes, and rapamycin treatment partially restores normal hepatic gene expression and nuclear localization of the transcription factor Hnf4a.","method":"Forward genetic screen, positional cloning, CRISPR/Cas9 knockout in zebrafish, rapamycin rescue, mTORC1 pathway analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen plus CRISPR KO with pathway rescue, single lab","pmids":["32518161"],"is_preprint":false},{"year":2022,"finding":"RBM15 forms liquid-like phase-separated condensates (droplets) in the nucleus in a protein/salt/RNA concentration-dependent manner, with condensates partially co-localizing with m6A-modified transcripts. RBM15 preferentially binds to and promotes m6A modification on STYK1 mRNA, enhancing its stability and leading to MAPK hyperactivation and oncogenic transformation of NIH3T3 cells.","method":"Super-resolution structured illumination microscopy (SIM), in vitro phase separation assays, MeRIP-seq, RNA-seq, NIH3T3 transformation assay","journal":"Computational and structural biotechnology journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phase separation reconstitution in vitro plus meRIP-seq and functional transformation assay, single lab","pmids":["36147665"],"is_preprint":false},{"year":2025,"finding":"L-lactate promotes lactylation of RBM15 at Lys850 (K850), mediated by MCT1-dependent lactate uptake. Lactylation at K850 stabilizes RBM15 by inhibiting proteasome-mediated ubiquitin degradation. HDAC3 acts as the delactylase for RBM15. K850R mutation disrupts the association between RBM15 and METTL3 and reduces global m6A levels, abrogating RBM15-mediated cell proliferation and migration.","method":"Mass spectrometry identification of lactylation sites, HDAC3 delactylase identification, K850R site-directed mutagenesis, co-immunoprecipitation (RBM15-METTL3), ubiquitination assay, m6A quantification","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM identification by MS plus mutagenesis and co-IP, single lab, multiple methods","pmids":["40135634"],"is_preprint":false},{"year":2025,"finding":"The RBM15-MKL1 fusion protein retains the RNA-binding and m6A-modifying functions of RBM15 while selectively regulating distinct mRNA targets including Frizzled genes in the Wnt signaling pathway. METTL3 inhibition (STM3675) decreases m6A deposition, induces apoptosis in RM-AMKL cells in vitro, and prolongs survival in transplanted mice. Direct Frizzled knockdown reduces RM-AMKL growth in vitro and in vivo.","method":"Multi-omics (transcriptome-wide RNA binding, m6A mapping, RNA turnover), METTL3 inhibitor treatment, Frizzled knockdown, in vivo transplantation model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multi-omic approach with pharmacological and genetic validation in vitro and in vivo, peer-reviewed","pmids":["40435410"],"is_preprint":false},{"year":2025,"finding":"RBM15 promotes m6A modification of SRSF1 mRNA by recruiting YTHDF3, increasing SRSF1 stability. Elevated SRSF1 then promotes ATP7B exon 21 alternative splicing, inhibiting cuproptosis and promoting NSCLC cell proliferation.","method":"RIP assay, MeRIP assay, xenograft tumor model, alternative splicing analysis, shRNA knockdown","journal":"The Kaohsiung journal of medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP/MeRIP plus functional assays in a single lab with limited mechanistic depth on the YTHDF3 recruitment step","pmids":["40923717"],"is_preprint":false}],"current_model":"RBM15 is an RNA-binding protein (spen family, with N-terminal RRM domains and a C-terminal SPOC domain) that functions as a non-catalytic adaptor subunit of the METTL3/WTAP m6A writer complex, recruiting the complex to specific target mRNAs via its RRM-mediated RNA binding; it also facilitates nuclear mRNA export by bridging NXF1-containing mRNPs to the DBP5 helicase at the nuclear pore, modulates Notch signaling via direct interaction with RBPJkappa, regulates alternative splicing by binding pre-mRNA introns and recruiting SF3B1, is subject to PRMT1-mediated arginine methylation at R578 leading to CNOT4-dependent ubiquitin degradation, is stabilized by lactylation at K850 (reversed by HDAC3), interacts with Setd1b histone methyltransferase via its SPOC domain, forms phase-separated nuclear condensates that co-localize with m6A-modified transcripts, and is essential for hematopoietic stem cell quiescence, B lymphopoiesis, placental vascular branching morphogenesis, and Xist-mediated X chromosome silencing."},"narrative":{"mechanistic_narrative":"RBM15 (OTT1) is a spen-family RNA-binding protein with N-terminal RRM domains and a C-terminal SPOC domain that functions as the mRNA-binding adaptor of the m6A methyltransferase writer complex, coupling RNA recognition to post-transcriptional and epigenetic regulation in hematopoietic and developmental contexts [PMID:11431691, PMID:29535189]. As an adaptor, RBM15 bridges target mRNAs to the WTAP/METTL3 machinery — a role established genetically through ZC3H13/Flacc-mediated linkage of Rbm15/Nito to the WTAP component [PMID:29535189] — and directs m6A deposition onto specific transcripts to control their fate, including degradation of BAF155 mRNA in a METTL3-dependent manner [PMID:31020615] and stabilization of STYK1 mRNA driving MAPK activation [PMID:36147665]. Beyond methylation, RBM15 regulates alternative splicing by binding pre-mRNA introns of megakaryopoietic genes (GATA1, RUNX1, TAL1, c-MPL) and recruiting SF3B1, and it generates a dominant-negative c-Mpl isoform while modifying H3K4me3 and H4 acetylation at the c-Mpl locus together with Setd1b (KMT2G) and HDAC3 [PMID:25468569, PMID:26575292]. It also acts at the nuclear envelope as an NXF1 cofactor that bridges mRNPs to the DBP5 helicase to drive efficient mRNA nuclear export [PMID:19786495]. RBM15 protein abundance is tightly controlled: PRMT1 methylates R578 to trigger CNOT4-dependent ubiquitin degradation [PMID:26575292], whereas lactylation at K850 stabilizes the protein, is reversed by HDAC3, and is required for the RBM15-METTL3 association [PMID:40135634]. Physiologically, RBM15 is essential for B lymphopoiesis and restrains myeloid/megakaryocytic expansion and HSC numbers [PMID:17376872], required for placental vascular branching morphogenesis during embryogenesis [PMID:18981216], and necessary for Xist-mediated X chromosome silencing through recruitment to the Xist A-repeat and 5' m6A region [PMID:26190105, PMID:32258426]. The recurrent t(1;22) RBM15-MKL1 fusion of acute megakaryoblastic leukemia deregulates RBPJ/Notch transcription and, retaining RNA-binding and m6A functions, redirects the writer complex onto distinct targets including Wnt-pathway Frizzled mRNAs, conferring METTL3-inhibitor sensitivity [PMID:19287095, PMID:40435410].","teleology":[{"year":2001,"claim":"Establishing that RBM15 is an RRM-containing spen-family protein recurrently fused to MKL1 in t(1;22) acute megakaryoblastic leukemia first linked the gene to RNA binding and to leukemogenesis.","evidence":"Molecular cloning and sequencing of translocation breakpoints","pmids":["11431691"],"confidence":"High","gaps":["Did not define the molecular function of the RRM domains","Mechanism by which the fusion transforms cells unknown"]},{"year":2007,"claim":"Conditional deletion in mice defined RBM15 as physiologically required for B lymphopoiesis while restraining myeloid/megakaryocytic lineages and the HSC compartment, anchoring its role in hematopoietic differentiation.","evidence":"Conditional knockout mouse, flow cytometry, bone marrow analysis","pmids":["17376872"],"confidence":"High","gaps":["Molecular targets driving lineage skewing not identified","Did not connect phenotype to a specific biochemical activity"]},{"year":2007,"claim":"Identification of RBPJkappa co-immunoprecipitation and cell-type-specific modulation of Notch-induced HES1 transcription connected RBM15 to a defined signaling transcription factor.","evidence":"RNAi, enforced expression, co-IP, luciferase reporters","pmids":["17283045"],"confidence":"Medium","gaps":["Basis of opposite effects in hematopoietic vs non-hematopoietic cells unresolved","Direct vs indirect RBPJkappa contact not mapped"]},{"year":2008,"claim":"A trophoblast-sparing genetic rescue established a tissue-specific developmental requirement, showing RBM15 is essential for placental vascular branching morphogenesis and embryonic survival.","evidence":"Germline/conditional KO with conditional rescue and expression profiling","pmids":["18981216"],"confidence":"High","gaps":["Downstream effectors of the vascular defect not defined","Link to RNA-level mechanism absent"]},{"year":2009,"claim":"Reciprocal binding and knockdown experiments placed RBM15 at the nuclear pore as an NXF1 cofactor that bridges mRNPs to the DBP5 helicase, defining a direct role in mRNA nuclear export.","evidence":"Co-IP, RIP, siRNA knockdown, fractionation, immunofluorescence","pmids":["19786495"],"confidence":"High","gaps":["RNA selectivity of export function not delineated","Relationship between export and later m6A roles unaddressed"]},{"year":2009,"claim":"A knockin model demonstrated that the RBM15-MKL1 fusion deregulates RBPJ-dependent Notch transcription and cooperates with MPL mutation to drive AMKL, mechanistically tying the fusion to malignant megakaryopoiesis.","evidence":"Knockin mouse, reporter assays, genetic cooperation with MPL","pmids":["19287095"],"confidence":"High","gaps":["RNA-binding contribution of the fusion not yet examined","Direct fusion targets not catalogued"]},{"year":2012,"claim":"Domain mapping showed the RBM15 SPOC domain directly binds the Setd1b (KMT2G) H3K4 methyltransferase and that this interaction is required for cytokine-independent AMKL proliferation, linking RBM15 to chromatin modification.","evidence":"Co-IP, domain mapping, growth assays with SPOC mutants","pmids":["22927943"],"confidence":"Medium","gaps":["Genomic loci of Setd1b recruitment not defined here","Single-lab interaction"]},{"year":2014,"claim":"Coupling RNA binding to chromatin marks, RBM15 was shown to control c-Mpl alternative splicing into a dominant-negative isoform while binding c-Mpl RNA and chromatin and regulating H3K4me3/H4 acetylation with Hdac3 and Setd1b.","evidence":"Conditional KO, splicing analysis, ChIP, RIP, histone modification assays","pmids":["25468569"],"confidence":"High","gaps":["Generality of RNA+chromatin coupling beyond c-Mpl untested","Splicing machinery recruited not identified in this study"]},{"year":2015,"claim":"RBM15 was shown to bind pre-mRNA introns of megakaryopoietic genes and recruit SF3B1, and its abundance to be controlled by PRMT1 methylation at R578 driving CNOT4-dependent degradation, defining both a splicing mechanism and a regulatory degradation axis.","evidence":"In vitro methylation/ubiquitylation assays, RIP, MS, R578 mutagenesis, rescue in AMKL lines","pmids":["26575292"],"confidence":"High","gaps":["How SF3B1 recruitment alters splice site choice not resolved","PRMT1 regulation outside megakaryopoiesis untested"]},{"year":2015,"claim":"An shRNA screen and super-resolution imaging identified RBM15 as required for Xist-mediated silencing and co-localizing with Xist RNA in the nuclear matrix, extending its function to X chromosome inactivation.","evidence":"shRNA screen, knockdown validation, 3D-SIM, allelic RNA-seq","pmids":["26190105"],"confidence":"Medium","gaps":["Mechanistic step in silencing not defined at this stage","Direct Xist contact not yet mapped"]},{"year":2016,"claim":"Discovery that the antisense AS-RBM15 lncRNA enhances cap-dependent RBM15 translation added a layer of RBM15 protein-level control independent of degradation.","evidence":"Overexpression/knockdown of AS-RBM15, translation reporters, domain mapping","pmids":["27118388"],"confidence":"Medium","gaps":["Physiological contexts where AS-RBM15 operates unknown","Single-lab finding"]},{"year":2018,"claim":"Cross-species co-IP and genetic epistasis established RBM15 as the mRNA-binding adaptor that links target transcripts to the WTAP/METTL3 m6A writer complex via ZC3H13/Flacc, redefining its core molecular identity.","evidence":"Reciprocal co-IP in Drosophila and mouse, m6A quantification, sex-determination epistasis","pmids":["29535189"],"confidence":"High","gaps":["Sequence determinants of RBM15 target selection not defined","How adaptor role integrates with export/splicing roles unclear"]},{"year":2020,"claim":"CRISPR deletion of the Xist A-repeat plus interactome MS showed RBM15 is recruited to the Xist A-repeat to direct 5' m6A deposition and partners with both the m6A and SETD1B complexes, mechanistically uniting its RNA-methylation and chromatin roles at Xist.","evidence":"CRISPR A-repeat deletion, m6A-seq, allelic RNA-seq, epitope-tag MS/MS","pmids":["32258426"],"confidence":"High","gaps":["Causal contribution of 5' m6A to silencing not isolated","Stoichiometry of dual complex association unknown"]},{"year":2019,"claim":"RBM15 was shown to bind BAF155 mRNA and drive its METTL3-dependent degradation, controlling cortical radial glial progenitor delamination and demonstrating target-specific m6A-mediated decay in neural development.","evidence":"RIP, CRISPR/shRNA in vitro and in vivo, overexpression, METTL3 dependence","pmids":["31020615"],"confidence":"Medium","gaps":["Single target focus; broader neural m6A program undefined","Recruitment specificity to BAF155 not mapped"]},{"year":2020,"claim":"A zebrafish forward-genetic screen revealed RBM15 is required specifically for liver maturation via restraint of mTORC1 and proper Hnf4a nuclear localization, broadening its developmental role beyond hematopoiesis and placenta.","evidence":"Forward screen, positional cloning, CRISPR KO, rapamycin rescue","pmids":["32518161"],"confidence":"Medium","gaps":["Molecular link between RBM15 and mTORC1 unknown","Whether effect is m6A-dependent untested"]},{"year":2022,"claim":"In vitro reconstitution showed RBM15 forms RNA/protein-concentration-dependent liquid-like nuclear condensates that co-localize with m6A transcripts and promotes m6A on STYK1 mRNA to drive oncogenic MAPK activation, adding a biophysical organizing principle to its writer-adaptor function.","evidence":"SIM imaging, in vitro phase separation, MeRIP-seq, RNA-seq, NIH3T3 transformation","pmids":["36147665"],"confidence":"Medium","gaps":["In vivo functional requirement of condensates not established","Determinants of STYK1 selectivity unclear"]},{"year":2025,"claim":"Identification of MCT1/lactate-driven K850 lactylation that stabilizes RBM15 and is reversed by HDAC3 — and is required for RBM15-METTL3 association — defined a metabolic input controlling RBM15 abundance and m6A output.","evidence":"MS lactylation mapping, HDAC3 delactylase assays, K850R mutagenesis, co-IP, ubiquitination/m6A assays","pmids":["40135634"],"confidence":"Medium","gaps":["Physiological/disease contexts of lactylation untested","Single-lab PTM characterization"]},{"year":2025,"claim":"Multi-omic and pharmacologic analyses showed the RBM15-MKL1 fusion retains RNA-binding/m6A activity but redirects it onto distinct targets including Wnt-pathway Frizzled mRNAs, conferring METTL3-inhibitor and Frizzled-knockdown vulnerability in AMKL.","evidence":"Transcriptome-wide RNA binding, m6A mapping, RNA turnover, METTL3 inhibitor, Frizzled knockdown, transplantation","pmids":["40435410"],"confidence":"High","gaps":["How fusion alters target selection relative to wild-type not fully resolved","Generalizability across AMKL subtypes untested"]},{"year":null,"claim":"The sequence and structural determinants by which RBM15 selects specific target mRNAs — and how its export, splicing, m6A-adaptor, and condensate functions are coordinated on a given transcript — remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined RNA sequence/structure code for RBM15 target choice","Integration of multiple molecular activities on single transcripts unmapped","Structural basis of SPOC-mediated complex assembly incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,8,12,15,17,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,13,17,19]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,12,15,17]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,7,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,6,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,7,21]}],"complexes":["m6A methyltransferase (METTL3/WTAP) writer complex","SETD1B (KMT2G) histone methyltransferase complex"],"partners":["METTL3","WTAP","ZC3H13","SETD1B","HDAC3","SF3B1","DBP5","NXF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96T37","full_name":"RNA-binding protein 15","aliases":["One-twenty two protein 1","RNA-binding motif protein 15"],"length_aa":977,"mass_kda":107.2,"function":"RNA-binding protein that acts as a key regulator of N6-methyladenosine (m6A) methylation of RNAs, thereby regulating different processes, such as hematopoietic cell homeostasis, alternative splicing of mRNAs and X chromosome inactivation mediated by Xist RNA (PubMed:27602518). Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing (By similarity). Plays a key role in m6A methylation, possibly by binding target RNAs and recruiting the WMM complex (PubMed:27602518). Involved in random X inactivation mediated by Xist RNA: acts by binding Xist RNA and recruiting the WMM complex, which mediates m6A methylation, leading to target YTHDC1 reader on Xist RNA and promoting transcription repression activity of Xist (PubMed:27602518). Required for the development of multiple tissues, such as the maintenance of the homeostasis of long-term hematopoietic stem cells and for megakaryocyte (MK) and B-cell differentiation (By similarity). Regulates megakaryocyte differentiation by regulating alternative splicing of genes important for megakaryocyte differentiation; probably regulates alternative splicing via m6A regulation (PubMed:26575292). Required for placental vascular branching morphogenesis and embryonic development of the heart and spleen (By similarity). Acts as a regulator of thrombopoietin response in hematopoietic stem cells by regulating alternative splicing of MPL (By similarity). May also function as an mRNA export factor, stimulating export and expression of RTE-containing mRNAs which are present in many retrotransposons that require to be exported prior to splicing (PubMed:17001072, PubMed:19786495). High affinity binding of pre-mRNA to RBM15 may allow targeting of the mRNP to the export helicase DBP5 in a manner that is independent of splicing-mediated NXF1 deposition, resulting in export prior to splicing (PubMed:17001072, PubMed:19786495). May be implicated in HOX gene regulation (PubMed:11344311)","subcellular_location":"Nucleus speckle; Nucleus, nucleoplasm; Nucleus envelope; Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/Q96T37/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM15","classification":"Not 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RBM15B","url":"https://www.omim.org/entry/612602"},{"mim_id":"612588","title":"BCL2-ASSOCIATED TRANSCRIPTION FACTOR 1; BCLAF1","url":"https://www.omim.org/entry/612588"},{"mim_id":"612472","title":"METHYLTRANSFERASE 3, N6-ADENOSINE-METHYLTRANSFERASE COMPLEX CATALYTIC SUBUNIT; METTL3","url":"https://www.omim.org/entry/612472"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/21270308","citation_count":5,"is_preprint":false},{"pmid":"40682199","id":"PMC_40682199","title":"RBM15 promotes hypoxia/reoxygenation-induced ferroptosis in human cardiomyocytes by mediating m6A modification of ACSL4.","date":"2025","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/40682199","citation_count":4,"is_preprint":false},{"pmid":"39527319","id":"PMC_39527319","title":"RBM15-mediated the m6A modification of MAT2A promotes osteosarcoma cell proliferation, metastasis and suppresses ferroptosis.","date":"2024","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39527319","citation_count":4,"is_preprint":false},{"pmid":"40636291","id":"PMC_40636291","title":"RNA Binding Motif Protein 15 (RBM15): Structure, Function and Its Research Progress in Tumors.","date":"2025","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40636291","citation_count":3,"is_preprint":false},{"pmid":"39659928","id":"PMC_39659928","title":"RBM15 increase tumor-infiltrating CD4+ T cell in ESCC via modulating of PLOD3.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39659928","citation_count":3,"is_preprint":false},{"pmid":"40464812","id":"PMC_40464812","title":"RBM15 promotes m6A methylation and stability of KLF6 mRNA to accelerate pyroptosis of retinal ganglion cells in early-stage diabetic retinopathy.","date":"2025","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/40464812","citation_count":3,"is_preprint":false},{"pmid":"39206850","id":"PMC_39206850","title":"RBM15 Promotes High Glucose-Induced Lens Epithelial Cell Injury by Inducing PRNP N6-Methyladenine Modification During Diabetic Cataract.","date":"2024","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/39206850","citation_count":3,"is_preprint":false},{"pmid":"38374236","id":"PMC_38374236","title":"Myeloid sarcoma with RBM15::MRTFA (MKL1) mimicking vascular neoplasm.","date":"2024","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38374236","citation_count":3,"is_preprint":false},{"pmid":"40370450","id":"PMC_40370450","title":"RBM15-mediated metabolic reprogramming boosts immune response in colorectal cancer.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40370450","citation_count":2,"is_preprint":false},{"pmid":"40883807","id":"PMC_40883807","title":"RBM15 promotes COAD progression by regulating the m6A modification of TMC5.","date":"2025","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/40883807","citation_count":2,"is_preprint":false},{"pmid":"40049430","id":"PMC_40049430","title":"RBM15 relies on m6A modification to inhibit UBE2C, alleviating hippocampal neuronal injury by limiting microglial inflammation.","date":"2025","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/40049430","citation_count":2,"is_preprint":false},{"pmid":"40923717","id":"PMC_40923717","title":"RBM15 Mediated m6A Modification of SRSF1 Inhibits Cuproptosis in Non-Small Cell Lung Cancer by Mediating ATP7B Alternative Splicing.","date":"2025","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40923717","citation_count":2,"is_preprint":false},{"pmid":"39701357","id":"PMC_39701357","title":"Mechanism of RBM15 in the malignant proliferation of colorectal cancer cells through regulating the stability of LncRNA FGD5-AS1 via m6A modification.","date":"2024","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39701357","citation_count":2,"is_preprint":false},{"pmid":"39840822","id":"PMC_39840822","title":"m6A Methylation Regulator RBM15-Mediated Upregulation of ITGBL1 mRNA Stability Aggravates Colon Adenocarcinoma Progression by Remodeling the Tumor Microenvironment.","date":"2025","source":"The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/39840822","citation_count":2,"is_preprint":false},{"pmid":"39556280","id":"PMC_39556280","title":"N6-Methyladenosine Modification of PERP by RBM15 Enhances the Tumorigenesis of Lung Adenocarcinoma via p53 Signaling Pathway.","date":"2024","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39556280","citation_count":2,"is_preprint":false},{"pmid":"40371234","id":"PMC_40371234","title":"lncSLERT Promotes Liver Metastasis in Colorectal Cancer by Down-Regulating HUNK Expression via RBM15-Mediated m6A Modification.","date":"2025","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40371234","citation_count":2,"is_preprint":false},{"pmid":"41674656","id":"PMC_41674656","title":"RBM15 in diseases: Molecular mechanisms and clinical opportunities from RNA m6A methylation.","date":"2025","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41674656","citation_count":1,"is_preprint":false},{"pmid":"40614597","id":"PMC_40614597","title":"RBM15-mediated m6A methylation of Entpd1/CD39 regulates extracellular ATP hydrolysis and alleviates myocardial ischemia-reperfusion injury.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40614597","citation_count":1,"is_preprint":false},{"pmid":"41403702","id":"PMC_41403702","title":"RBM15-mediated m6A modification in cancer progression and tumor immunity: molecular mechanisms and therapeutic potential.","date":"2025","source":"Frontiers in cell and developmental 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motif (RRM)-containing protein with homology to Drosophila spen, fused to MKL1 in the t(1;22)(p13;q13) translocation of acute megakaryoblastic leukemia.\",\n      \"method\": \"Molecular cloning and sequencing of translocation breakpoints\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — original discovery of the gene and fusion by molecular cloning, replicated in multiple subsequent studies\",\n      \"pmids\": [\"11431691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The OTT-MAL (RBM15-MKL1) fusion gene is present in all t(1;22) acute megakaryoblastic leukemia cases studied, with the translocation occurring via a non-homologous end joining mechanism involving a non-canonical topoisomerase II-like consensus sequence in the OTT gene.\",\n      \"method\": \"Nucleotide sequence analysis of translocation breakpoints, FISH, RT-PCR\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequence analysis of multiple breakpoints, single lab\",\n      \"pmids\": [\"11746984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RBM15 (OTT1) interacts via its SPOC domain with the Epstein-Barr virus mRNA export factor EB2, and this interaction is mechanistically linked to splicing regulation; OTT1 and SHARP SPOC domains interact with SMRT/NCoR corepressors but with far weaker repressive activity than SHARP.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, transcriptional repression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus co-IP, single lab, two orthogonal methods\",\n      \"pmids\": [\"16129689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RBM15 modulates Notch-induced HES1 promoter activity in a cell-type-specific manner: it inhibits Notch-induced HES1 transcription in non-hematopoietic cells but stimulates it in hematopoietic cell lines. The N-terminus of RBM15 co-immunoprecipitates with RBPJkappa, a critical Notch signaling transcription factor.\",\n      \"method\": \"RNA interference, enforced expression, co-immunoprecipitation, luciferase reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional assays with co-IP, single lab\",\n      \"pmids\": [\"17283045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Conditional deletion of Ott1 (Rbm15) in adult mice causes a block in pro/pre-B differentiation leading to loss of peripheral B cells, myeloid and megakaryocytic expansion, and increased Lin-Sca-1+c-Kit+ hematopoietic stem cells, establishing Ott1 as required for B lymphopoiesis and inhibitory in myeloid/megakaryocytic lineages.\",\n      \"method\": \"Conditional knockout mouse model, flow cytometry, bone marrow analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular phenotypes across multiple hematopoietic lineages, rigorous in vivo model\",\n      \"pmids\": [\"17376872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OTT (RBM15) interacts with histone deacetylase 3 (HDAC3), but this interaction is abolished in the OTT-BSAC fusion protein. OTT-BSAC, unlike BSAC alone, exclusively localizes to the nucleus (BSAC normally resides predominantly in cytoplasm), activating YY1-binding sequence-containing promoters.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/localization, luciferase reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus localization plus functional reporter assays, single lab\",\n      \"pmids\": [\"18667423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Germ-line deletion of Ott1 (Rbm15) causes embryonic lethality by E10.5 due to defects in placental vascular branching morphogenesis in spongiotrophoblast and syncytiotrophoblast layers. Trophoblast-specific rescue restores placenta and allows survival to term, revealing cardiac and splenic developmental abnormalities with enrichment of hypoxia-related gene expression changes.\",\n      \"method\": \"Germ-line and conditional knockout mouse models, conditional rescue with trophoblast-sparing Cre, global gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous genetic rescue experiment establishing tissue-specific requirement, multiple phenotypic readouts\",\n      \"pmids\": [\"18981216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The OTT-MAL (RBM15-MKL1) fusion oncogene deregulates transcriptional activity of the Notch signaling pathway transcription factor RBPJ, causing abnormal fetal megakaryopoiesis; cooperation with activating MPL mutation efficiently induces short-latency AMKL in a knockin mouse model.\",\n      \"method\": \"Knockin mouse model, transcriptional reporter assays, genetic cooperation experiments with MPL mutation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockin model with mechanistic transcription pathway analysis and genetic epistasis, replicated concept from Ma et al. 2007\",\n      \"pmids\": [\"19287095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RBM15 binds specifically to the RNA helicase DBP5 and facilitates DBP5's direct contact with mRNA in vivo. RBM15 localizes to the nuclear envelope where it co-localizes with DBP5 and NXF1. Gene silencing of RBM15 leads to cytoplasmic depletion and nuclear accumulation of bulk mRNA and specific endogenous transcripts, establishing RBM15 as required for efficient mRNA nuclear export.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, siRNA knockdown, subcellular fractionation, immunofluorescence\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays plus functional knockdown with mRNA export phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"19786495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RBM15 and OTT3 (RBM15B) function as cellular NXF1 cofactors; knockdown of RBM15 leads to nuclear export deficiency of KSHV ORF57 RNA. KSHV ORF57 interacts directly with the RBM15 C-terminal SPOC domain to reduce RBM15 binding to ORF59 RNA.\",\n      \"method\": \"RNAi knockdown, RNA FISH, co-immunoprecipitation, subcellular RNA fractionation\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction mapping with SPOC domain plus functional knockdown phenotype, single lab\",\n      \"pmids\": [\"21106733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RBM15 and the leukemogenic RBM15-MKL1 fusion protein directly interact with the Setd1b histone H3-Lys4 methyltransferase (KMT2G) via the RBM15 SPOC domain and the Setd1b LSD motif. Cytokine-independent proliferation of AMKL cells requires an intact RBM15 SPOC domain mediating this interaction.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping experiments, cytokine-independent growth assays with SPOC domain mutants\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction with domain mapping plus functional consequence, single lab\",\n      \"pmids\": [\"22927943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ott1 (Rbm15) controls alternative splicing of c-Mpl to generate a dominant-negative isoform (Mpl-TR) that inhibits HSC engraftment and attenuates Thpo signaling. Ott1 associates with Hdac3 and the histone methyltransferase Setd1b, binds both c-Mpl RNA and chromatin, and regulates H4 acetylation and H3K4me3 marks at the c-Mpl locus.\",\n      \"method\": \"Conditional KO mouse model, alternative splicing analysis, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), histone modification assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO, RIP, ChIP, splicing analysis) in single rigorous study establishing epigenetic mechanism\",\n      \"pmids\": [\"25468569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBM15 is methylated by PRMT1 at residue R578, which leads to its ubiquitin-mediated degradation via the E3 ligase CNOT4. RBM15 binds to pre-mRNA intronic regions of megakaryopoiesis-related genes (GATA1, RUNX1, TAL1, c-MPL) and recruits the splicing factor SF3B1 to the same intronic sites, regulating alternative splicing. PRMT1 overexpression blocks megakaryocyte differentiation by downregulating RBM15 protein; restoring RBM15 rescues differentiation.\",\n      \"method\": \"In vitro methylation assay, ubiquitylation assay, RNA immunoprecipitation (RIP), mass spectrometry, site-directed mutagenesis (R578), rescue experiments in AMKL cell lines\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assays with mutagenesis plus RIP and functional rescue, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"26575292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A pooled shRNA screen identified RBM15 as required for Xist RNA-mediated silencing in X chromosome inactivation. RBM15 co-localizes with Xist RNA within the nuclear matrix subcompartment as shown by super-resolution 3D-SIM microscopy.\",\n      \"method\": \"shRNA screen, validation by knockdown, super-resolution 3D-SIM immunofluorescence microscopy, allelic RNA-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — screen plus validation with direct localization evidence, single lab\",\n      \"pmids\": [\"26190105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AS-RBM15, an antisense RNA transcribed from within exon 1 of RBM15, enhances RBM15 protein translation in a CAP-dependent manner. The region of AS-RBM15 overlapping with the 5'UTR of RBM15 is sufficient for upregulation of RBM15 protein translation.\",\n      \"method\": \"Overexpression and knockdown of AS-RBM15, translation reporter assays, domain mapping\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional domain mapping with CAP-dependent translation assays, single lab — NOTE: this paper is about the AS-RBM15 lncRNA regulating RBM15 protein; included because the mechanism directly establishes RBM15 protein level control\",\n      \"pmids\": [\"27118388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Zc3h13/Flacc promotes m6A deposition by bridging the WTAP/Fl(2)d component of the m6A methyltransferase complex to the mRNA-binding factor Rbm15/Nito (Spenito), establishing RBM15 as the mRNA-binding adaptor that links target mRNAs to the METTL3 writer complex.\",\n      \"method\": \"Co-immunoprecipitation in Drosophila and mouse, m6A quantification, genetic analysis of sex determination pathway (epistasis), protein interaction mapping\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP across two species plus epistatic genetic analysis and functional m6A quantification, multi-lab relevant finding\",\n      \"pmids\": [\"29535189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RBM15, as a subunit of the m6A methyltransferase complex, interacts with BAF155 mRNA and mediates its degradation through the mRNA methylation machinery in a METTL3-dependent manner. RBM15 ablation in neuronal cells and developing cortex increases BAF155 expression; RBM15 overexpression decreases BAF155 mRNA/protein and perturbs BAF155-dependent transcriptional activity and apical radial glial progenitor delamination.\",\n      \"method\": \"RIP assay, CRISPR/shRNA loss-of-function in vitro and in vivo, overexpression experiments, m6A pathway functional dependence on METTL3\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus in vivo CRISPR KO with defined phenotype and pathway epistasis (METTL3 dependence), single lab\",\n      \"pmids\": [\"31020615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RBM15 binds to the Xist A-repeat region; deletion of the Xist A-repeat entirely abolishes m6A deposition in the Xist 5' m6A region without affecting exon VII m6A. In mESCs, RBM15 interacts with the m6A methyltransferase complex and with the SETD1B histone-modifying complex, plus several RNA metabolism proteins, as determined by epitope-tag purification and MS/MS.\",\n      \"method\": \"CRISPR/Cas9 deletion of Xist A-repeat, m6A-seq, allelic RNA-seq, epitope-tag purification followed by MS/MS interactome analysis\",\n      \"journal\": \"Wellcome open research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR mutagenesis with m6A-seq readout plus MS/MS interactome, multiple orthogonal methods establishing RBM15 recruitment to Xist 5' m6A region\",\n      \"pmids\": [\"32258426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of Rbm15 in zebrafish (cq96 mutant identified by forward genetic screen) causes a specific defect in liver maturation without affecting hepatoblast specification, differentiation, or hepatocyte proliferation/apoptosis. The mTORC1 pathway is hyperactivated in rbm15-deficient hepatocytes, and rapamycin treatment partially restores normal hepatic gene expression and nuclear localization of the transcription factor Hnf4a.\",\n      \"method\": \"Forward genetic screen, positional cloning, CRISPR/Cas9 knockout in zebrafish, rapamycin rescue, mTORC1 pathway analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen plus CRISPR KO with pathway rescue, single lab\",\n      \"pmids\": [\"32518161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM15 forms liquid-like phase-separated condensates (droplets) in the nucleus in a protein/salt/RNA concentration-dependent manner, with condensates partially co-localizing with m6A-modified transcripts. RBM15 preferentially binds to and promotes m6A modification on STYK1 mRNA, enhancing its stability and leading to MAPK hyperactivation and oncogenic transformation of NIH3T3 cells.\",\n      \"method\": \"Super-resolution structured illumination microscopy (SIM), in vitro phase separation assays, MeRIP-seq, RNA-seq, NIH3T3 transformation assay\",\n      \"journal\": \"Computational and structural biotechnology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phase separation reconstitution in vitro plus meRIP-seq and functional transformation assay, single lab\",\n      \"pmids\": [\"36147665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"L-lactate promotes lactylation of RBM15 at Lys850 (K850), mediated by MCT1-dependent lactate uptake. Lactylation at K850 stabilizes RBM15 by inhibiting proteasome-mediated ubiquitin degradation. HDAC3 acts as the delactylase for RBM15. K850R mutation disrupts the association between RBM15 and METTL3 and reduces global m6A levels, abrogating RBM15-mediated cell proliferation and migration.\",\n      \"method\": \"Mass spectrometry identification of lactylation sites, HDAC3 delactylase identification, K850R site-directed mutagenesis, co-immunoprecipitation (RBM15-METTL3), ubiquitination assay, m6A quantification\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM identification by MS plus mutagenesis and co-IP, single lab, multiple methods\",\n      \"pmids\": [\"40135634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The RBM15-MKL1 fusion protein retains the RNA-binding and m6A-modifying functions of RBM15 while selectively regulating distinct mRNA targets including Frizzled genes in the Wnt signaling pathway. METTL3 inhibition (STM3675) decreases m6A deposition, induces apoptosis in RM-AMKL cells in vitro, and prolongs survival in transplanted mice. Direct Frizzled knockdown reduces RM-AMKL growth in vitro and in vivo.\",\n      \"method\": \"Multi-omics (transcriptome-wide RNA binding, m6A mapping, RNA turnover), METTL3 inhibitor treatment, Frizzled knockdown, in vivo transplantation model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multi-omic approach with pharmacological and genetic validation in vitro and in vivo, peer-reviewed\",\n      \"pmids\": [\"40435410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM15 promotes m6A modification of SRSF1 mRNA by recruiting YTHDF3, increasing SRSF1 stability. Elevated SRSF1 then promotes ATP7B exon 21 alternative splicing, inhibiting cuproptosis and promoting NSCLC cell proliferation.\",\n      \"method\": \"RIP assay, MeRIP assay, xenograft tumor model, alternative splicing analysis, shRNA knockdown\",\n      \"journal\": \"The Kaohsiung journal of medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP/MeRIP plus functional assays in a single lab with limited mechanistic depth on the YTHDF3 recruitment step\",\n      \"pmids\": [\"40923717\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM15 is an RNA-binding protein (spen family, with N-terminal RRM domains and a C-terminal SPOC domain) that functions as a non-catalytic adaptor subunit of the METTL3/WTAP m6A writer complex, recruiting the complex to specific target mRNAs via its RRM-mediated RNA binding; it also facilitates nuclear mRNA export by bridging NXF1-containing mRNPs to the DBP5 helicase at the nuclear pore, modulates Notch signaling via direct interaction with RBPJkappa, regulates alternative splicing by binding pre-mRNA introns and recruiting SF3B1, is subject to PRMT1-mediated arginine methylation at R578 leading to CNOT4-dependent ubiquitin degradation, is stabilized by lactylation at K850 (reversed by HDAC3), interacts with Setd1b histone methyltransferase via its SPOC domain, forms phase-separated nuclear condensates that co-localize with m6A-modified transcripts, and is essential for hematopoietic stem cell quiescence, B lymphopoiesis, placental vascular branching morphogenesis, and Xist-mediated X chromosome silencing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM15 (OTT1) is a spen-family RNA-binding protein with N-terminal RRM domains and a C-terminal SPOC domain that functions as the mRNA-binding adaptor of the m6A methyltransferase writer complex, coupling RNA recognition to post-transcriptional and epigenetic regulation in hematopoietic and developmental contexts [#0, #15]. As an adaptor, RBM15 bridges target mRNAs to the WTAP/METTL3 machinery — a role established genetically through ZC3H13/Flacc-mediated linkage of Rbm15/Nito to the WTAP component [#15] — and directs m6A deposition onto specific transcripts to control their fate, including degradation of BAF155 mRNA in a METTL3-dependent manner [#16] and stabilization of STYK1 mRNA driving MAPK activation [#19]. Beyond methylation, RBM15 regulates alternative splicing by binding pre-mRNA introns of megakaryopoietic genes (GATA1, RUNX1, TAL1, c-MPL) and recruiting SF3B1, and it generates a dominant-negative c-Mpl isoform while modifying H3K4me3 and H4 acetylation at the c-Mpl locus together with Setd1b (KMT2G) and HDAC3 [#11, #12]. It also acts at the nuclear envelope as an NXF1 cofactor that bridges mRNPs to the DBP5 helicase to drive efficient mRNA nuclear export [#8]. RBM15 protein abundance is tightly controlled: PRMT1 methylates R578 to trigger CNOT4-dependent ubiquitin degradation [#12], whereas lactylation at K850 stabilizes the protein, is reversed by HDAC3, and is required for the RBM15-METTL3 association [#20]. Physiologically, RBM15 is essential for B lymphopoiesis and restrains myeloid/megakaryocytic expansion and HSC numbers [#4], required for placental vascular branching morphogenesis during embryogenesis [#6], and necessary for Xist-mediated X chromosome silencing through recruitment to the Xist A-repeat and 5' m6A region [#13, #17]. The recurrent t(1;22) RBM15-MKL1 fusion of acute megakaryoblastic leukemia deregulates RBPJ/Notch transcription and, retaining RNA-binding and m6A functions, redirects the writer complex onto distinct targets including Wnt-pathway Frizzled mRNAs, conferring METTL3-inhibitor sensitivity [#7, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that RBM15 is an RRM-containing spen-family protein recurrently fused to MKL1 in t(1;22) acute megakaryoblastic leukemia first linked the gene to RNA binding and to leukemogenesis.\",\n      \"evidence\": \"Molecular cloning and sequencing of translocation breakpoints\",\n      \"pmids\": [\"11431691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular function of the RRM domains\", \"Mechanism by which the fusion transforms cells unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Conditional deletion in mice defined RBM15 as physiologically required for B lymphopoiesis while restraining myeloid/megakaryocytic lineages and the HSC compartment, anchoring its role in hematopoietic differentiation.\",\n      \"evidence\": \"Conditional knockout mouse, flow cytometry, bone marrow analysis\",\n      \"pmids\": [\"17376872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets driving lineage skewing not identified\", \"Did not connect phenotype to a specific biochemical activity\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of RBPJkappa co-immunoprecipitation and cell-type-specific modulation of Notch-induced HES1 transcription connected RBM15 to a defined signaling transcription factor.\",\n      \"evidence\": \"RNAi, enforced expression, co-IP, luciferase reporters\",\n      \"pmids\": [\"17283045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis of opposite effects in hematopoietic vs non-hematopoietic cells unresolved\", \"Direct vs indirect RBPJkappa contact not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"A trophoblast-sparing genetic rescue established a tissue-specific developmental requirement, showing RBM15 is essential for placental vascular branching morphogenesis and embryonic survival.\",\n      \"evidence\": \"Germline/conditional KO with conditional rescue and expression profiling\",\n      \"pmids\": [\"18981216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of the vascular defect not defined\", \"Link to RNA-level mechanism absent\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Reciprocal binding and knockdown experiments placed RBM15 at the nuclear pore as an NXF1 cofactor that bridges mRNPs to the DBP5 helicase, defining a direct role in mRNA nuclear export.\",\n      \"evidence\": \"Co-IP, RIP, siRNA knockdown, fractionation, immunofluorescence\",\n      \"pmids\": [\"19786495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA selectivity of export function not delineated\", \"Relationship between export and later m6A roles unaddressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A knockin model demonstrated that the RBM15-MKL1 fusion deregulates RBPJ-dependent Notch transcription and cooperates with MPL mutation to drive AMKL, mechanistically tying the fusion to malignant megakaryopoiesis.\",\n      \"evidence\": \"Knockin mouse, reporter assays, genetic cooperation with MPL\",\n      \"pmids\": [\"19287095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding contribution of the fusion not yet examined\", \"Direct fusion targets not catalogued\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Domain mapping showed the RBM15 SPOC domain directly binds the Setd1b (KMT2G) H3K4 methyltransferase and that this interaction is required for cytokine-independent AMKL proliferation, linking RBM15 to chromatin modification.\",\n      \"evidence\": \"Co-IP, domain mapping, growth assays with SPOC mutants\",\n      \"pmids\": [\"22927943\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genomic loci of Setd1b recruitment not defined here\", \"Single-lab interaction\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Coupling RNA binding to chromatin marks, RBM15 was shown to control c-Mpl alternative splicing into a dominant-negative isoform while binding c-Mpl RNA and chromatin and regulating H3K4me3/H4 acetylation with Hdac3 and Setd1b.\",\n      \"evidence\": \"Conditional KO, splicing analysis, ChIP, RIP, histone modification assays\",\n      \"pmids\": [\"25468569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of RNA+chromatin coupling beyond c-Mpl untested\", \"Splicing machinery recruited not identified in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"RBM15 was shown to bind pre-mRNA introns of megakaryopoietic genes and recruit SF3B1, and its abundance to be controlled by PRMT1 methylation at R578 driving CNOT4-dependent degradation, defining both a splicing mechanism and a regulatory degradation axis.\",\n      \"evidence\": \"In vitro methylation/ubiquitylation assays, RIP, MS, R578 mutagenesis, rescue in AMKL lines\",\n      \"pmids\": [\"26575292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SF3B1 recruitment alters splice site choice not resolved\", \"PRMT1 regulation outside megakaryopoiesis untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"An shRNA screen and super-resolution imaging identified RBM15 as required for Xist-mediated silencing and co-localizing with Xist RNA in the nuclear matrix, extending its function to X chromosome inactivation.\",\n      \"evidence\": \"shRNA screen, knockdown validation, 3D-SIM, allelic RNA-seq\",\n      \"pmids\": [\"26190105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic step in silencing not defined at this stage\", \"Direct Xist contact not yet mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that the antisense AS-RBM15 lncRNA enhances cap-dependent RBM15 translation added a layer of RBM15 protein-level control independent of degradation.\",\n      \"evidence\": \"Overexpression/knockdown of AS-RBM15, translation reporters, domain mapping\",\n      \"pmids\": [\"27118388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts where AS-RBM15 operates unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cross-species co-IP and genetic epistasis established RBM15 as the mRNA-binding adaptor that links target transcripts to the WTAP/METTL3 m6A writer complex via ZC3H13/Flacc, redefining its core molecular identity.\",\n      \"evidence\": \"Reciprocal co-IP in Drosophila and mouse, m6A quantification, sex-determination epistasis\",\n      \"pmids\": [\"29535189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence determinants of RBM15 target selection not defined\", \"How adaptor role integrates with export/splicing roles unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CRISPR deletion of the Xist A-repeat plus interactome MS showed RBM15 is recruited to the Xist A-repeat to direct 5' m6A deposition and partners with both the m6A and SETD1B complexes, mechanistically uniting its RNA-methylation and chromatin roles at Xist.\",\n      \"evidence\": \"CRISPR A-repeat deletion, m6A-seq, allelic RNA-seq, epitope-tag MS/MS\",\n      \"pmids\": [\"32258426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal contribution of 5' m6A to silencing not isolated\", \"Stoichiometry of dual complex association unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"RBM15 was shown to bind BAF155 mRNA and drive its METTL3-dependent degradation, controlling cortical radial glial progenitor delamination and demonstrating target-specific m6A-mediated decay in neural development.\",\n      \"evidence\": \"RIP, CRISPR/shRNA in vitro and in vivo, overexpression, METTL3 dependence\",\n      \"pmids\": [\"31020615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single target focus; broader neural m6A program undefined\", \"Recruitment specificity to BAF155 not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A zebrafish forward-genetic screen revealed RBM15 is required specifically for liver maturation via restraint of mTORC1 and proper Hnf4a nuclear localization, broadening its developmental role beyond hematopoiesis and placenta.\",\n      \"evidence\": \"Forward screen, positional cloning, CRISPR KO, rapamycin rescue\",\n      \"pmids\": [\"32518161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between RBM15 and mTORC1 unknown\", \"Whether effect is m6A-dependent untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"In vitro reconstitution showed RBM15 forms RNA/protein-concentration-dependent liquid-like nuclear condensates that co-localize with m6A transcripts and promotes m6A on STYK1 mRNA to drive oncogenic MAPK activation, adding a biophysical organizing principle to its writer-adaptor function.\",\n      \"evidence\": \"SIM imaging, in vitro phase separation, MeRIP-seq, RNA-seq, NIH3T3 transformation\",\n      \"pmids\": [\"36147665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo functional requirement of condensates not established\", \"Determinants of STYK1 selectivity unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of MCT1/lactate-driven K850 lactylation that stabilizes RBM15 and is reversed by HDAC3 — and is required for RBM15-METTL3 association — defined a metabolic input controlling RBM15 abundance and m6A output.\",\n      \"evidence\": \"MS lactylation mapping, HDAC3 delactylase assays, K850R mutagenesis, co-IP, ubiquitination/m6A assays\",\n      \"pmids\": [\"40135634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological/disease contexts of lactylation untested\", \"Single-lab PTM characterization\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multi-omic and pharmacologic analyses showed the RBM15-MKL1 fusion retains RNA-binding/m6A activity but redirects it onto distinct targets including Wnt-pathway Frizzled mRNAs, conferring METTL3-inhibitor and Frizzled-knockdown vulnerability in AMKL.\",\n      \"evidence\": \"Transcriptome-wide RNA binding, m6A mapping, RNA turnover, METTL3 inhibitor, Frizzled knockdown, transplantation\",\n      \"pmids\": [\"40435410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How fusion alters target selection relative to wild-type not fully resolved\", \"Generalizability across AMKL subtypes untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The sequence and structural determinants by which RBM15 selects specific target mRNAs — and how its export, splicing, m6A-adaptor, and condensate functions are coordinated on a given transcript — remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined RNA sequence/structure code for RBM15 target choice\", \"Integration of multiple molecular activities on single transcripts unmapped\", \"Structural basis of SPOC-mediated complex assembly incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 8, 12, 15, 17, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 13, 17, 19]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 12, 15, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 7, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 6, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 7, 21]}\n    ],\n    \"complexes\": [\n      \"m6A methyltransferase (METTL3/WTAP) writer complex\",\n      \"SETD1B (KMT2G) histone methyltransferase complex\"\n    ],\n    \"partners\": [\n      \"METTL3\",\n      \"WTAP\",\n      \"ZC3H13\",\n      \"SETD1B\",\n      \"HDAC3\",\n      \"SF3B1\",\n      \"DBP5\",\n      \"NXF1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}