{"gene":"MEIS1","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1995,"finding":"MEIS1 was identified as a novel TALE-class homeobox gene whose homeodomain is most closely related to PBX/exd family proteins, suggesting cooperative binding with HOX proteins; viral integration at the Meis1 locus in BXH-2 murine myeloid leukemias produces an additional truncated transcript, implicating altered MEIS1 expression in myeloid leukemogenesis.","method":"Northern blot, cDNA cloning, retroviral insertional mutagenesis in BXH-2 mice","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — original discovery paper with multiple methods; replicated widely across subsequent labs","pmids":["7565694"],"is_preprint":false},{"year":1997,"finding":"MEIS1 proteins form heterodimeric DNA-binding complexes with AbdB-like HOX proteins (HOXA9, HOXA10, HOXA11, HOXD12, HOXB13) on a composite DNA target containing a MEIS1 site (TGACAG) and an AbdB-like HOX site; HOX proteins dramatically stabilize MEIS1 DNA binding, as shown by slower dissociation kinetics of the complex compared to MEIS1 alone.","method":"In vitro DNA-binding assay (EMSA), gel mobility shift, cooperative binding analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis-level dissection; foundational biochemistry replicated in multiple subsequent studies","pmids":["9343407"],"is_preprint":false},{"year":1997,"finding":"MEIS1 and its relative pKNOX1 dimerize with PBX1 on a TGATTGAC motif; the MEIS1/pKNOX1 interaction domain maps to a conserved N-terminal PBX domain that is deleted in the leukemic oncoprotein E2a-PBX1, explaining why MEIS1 fails to dimerize with E2a-PBX1. The interaction interface on MEIS1 is distinct from the tryptophan motif used by HOX proteins.","method":"EMSA, cooperative DNA-binding assays, deletion mapping, comparison with E2a-PBX1","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding reconstitution with domain mapping; replicated by multiple labs","pmids":["9405651"],"is_preprint":false},{"year":1998,"finding":"MEIS1 cooperatively binds the cAMP-responsive sequence CRS1 of bovine CYP17 together with PBX1; neither protein binds alone. Mutagenesis shows a dedicated MEIS1 binding site adjacent to the PBX site, and the conserved tryptophan N-terminal to the MEIS1 homeodomain is NOT required for Pbx cooperative binding, distinguishing the PBX-MEIS1 interaction from the PBX-HOX interaction. The interaction is evolutionarily conserved with Drosophila extradenticle and C. elegans ceh-20.","method":"CRS1 affinity chromatography purification of MEIS1 from adrenal cell extracts, EMSA, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis; identifies specific binding site and mechanism","pmids":["9525891"],"is_preprint":false},{"year":1998,"finding":"Homothorax (hth), the Drosophila orthologue of MEIS1, is required for nuclear localization of Extradenticle (EXD, orthologue of PBX); ectopic HTH drives ectopic nuclear EXD. In hth mutants, EXD protein remains cytoplasmic; in exd mutants, HTH protein levels are severely reduced, establishing a mutual dependency.","method":"Genetic epistasis in Drosophila, immunostaining, ectopic expression experiments","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic epistasis with protein localization readout; established mechanism conserved to vertebrates","pmids":["9463350"],"is_preprint":false},{"year":1999,"finding":"MEIS1 promotes nuclear import of PBX1 in vertebrate limb cells; Meis1/2 expression is restricted to the proximal limb domain coinciding with nuclear PBX1; ectopic Meis1 in chicken limb or hth in Drosophila abolishes distal limb structures and causes distal-to-proximal identity transformations, demonstrating that restriction of Meis1/Hth to proximal regions is essential for proximodistal limb patterning.","method":"In situ hybridization, immunostaining, ectopic overexpression in chick and Drosophila, Drosophila genetics","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiments tied to functional consequence; multiple organisms and orthogonal methods","pmids":["10586884"],"is_preprint":false},{"year":1999,"finding":"HOXA9, PBX2, and MEIS1 form trimeric complexes in myeloid cell nuclei: MEIS1 enhances in vitro HOXA9-PBX protein complex formation in the absence of DNA and forms a trimeric EMSA complex on PBX-HOXA9 oligonucleotides. Immunoprecipitation of HOXA9 from myeloid cell extracts co-precipitates PBX2 and MEIS1. The three proteins co-localize in nuclear speckles.","method":"In vitro EMSA, co-immunoprecipitation from myeloid cell nuclear extracts, immunofluorescence co-localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution of trimeric complex plus reciprocal co-IP from endogenous cell extracts","pmids":["10082572"],"is_preprint":false},{"year":1999,"finding":"Pbx-Meis1/Prep1 heterodimers bind DNA cooperatively with myogenic bHLH transcription factors (MyoD, myogenin, Mrf-4, Myf-5) through a conserved tryptophan motif N-terminal to the bHLH DNA-binding domain; this tryptophan motif is required for MyoD to remodel chromatin at the Myogenin promoter and activate Myogenin transcription in vivo.","method":"EMSA, tryptophan motif mutagenesis, chromatin remodeling assay, transactivation assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution plus mutagenesis with in vivo functional validation","pmids":["10471746"],"is_preprint":false},{"year":2001,"finding":"MEIS1 genetically collaborates with both HOXA9 and HOXB3 to induce AML, but PREP1 overexpression cannot substitute for MEIS1 in HOXA9-induced AML despite shared ability to retain PBX in the nucleus, demonstrating that MEIS1 leukemogenic function extends beyond PBX nuclear retention.","method":"Murine bone marrow transplantation leukemia model, retroviral overexpression, genetic epistasis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean genetic epistasis in primary cells/mice; replicated in subsequent studies","pmids":["11113197"],"is_preprint":false},{"year":2003,"finding":"MEIS1, PBX1B, and PBX2 bind as MEIS1/PBX complexes to the TME (tandem repeat of MEIS1 binding element) in the platelet factor 4 (PF4) promoter to activate PF4 transcription in megakaryocytic cells; disruption of MEIS1 binding sites reduces promoter activity by approximately half in megakaryocytic HEL cells.","method":"EMSA, DNA affinity chromatography, Western blot, supershift assay, promoter reporter assay, dominant-negative inhibition","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical purification of binding proteins, EMSA, mutagenesis of binding sites, functional reporter assay","pmids":["12609849"],"is_preprint":false},{"year":2004,"finding":"Meis1-deficient mouse embryos die by E14.5 with failure to produce megakaryocytes, extensive hemorrhaging, lack of well-formed capillaries, and severely reduced colony-forming hematopoietic cells; Meis1-/- fetal liver cells fail to radioprotect irradiated mice and compete poorly in repopulation assays, establishing Meis1 as required for definitive hematopoiesis, megakaryocyte production, angiogenesis, and hematopoietic stem cell function.","method":"Germline knockout mouse, fetal liver transplantation, radioprotection assay, competitive repopulation, histology","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple specific phenotypic readouts; replicated in independent KO studies","pmids":["14713950"],"is_preprint":false},{"year":2004,"finding":"Hoxa9 and Meis1 are key transcriptional targets upregulated by MLL-ENL; enforced co-expression of Hoxa9 with Meis1 is sufficient to substitute for MLL-ENL function and maintain continuous proliferation and differentiation arrest of hematopoietic cells.","method":"Inducible MLL-ENL-ERtm system, microarray expression profiling, retroviral co-expression, proliferation and differentiation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — conditional MLL fusion system combined with gain-of-function reconstitution; replicated widely","pmids":["14701735"],"is_preprint":false},{"year":2005,"finding":"Meis1 programs expression of FLT3 and CD34 (HSC-specific genes) in Hoxa9-immortalized myeloid progenitors, converting them to AML-initiating cells. Meis1 leukemogenic activity requires PBX binding, DNA binding, and a conserved C-terminal tail function. Meis1 establishes leukemia stem cell character through induction of HSC-associated genes.","method":"Retroviral transduction, in vitro progenitor culture, leukemia transplantation assay, domain deletion mutants","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — structure-function with multiple deletion mutants, in vivo leukemia assay, gene expression readout","pmids":["15755900"],"is_preprint":false},{"year":2006,"finding":"A dominant transactivating VP16-Meis1 fusion acts as an autonomous oncogene without co-expressed HOX genes and all resulting leukemias show activation of endogenous Hoxa9/Hoxa7, indicating HOX gene activation is a key downstream event. ChIP confirmed co-occupancy of Hoxa9 and Meis1 on the Flt3 promoter, demonstrating Meis1-Pbx and Hox-Pbx complexes co-occupy leukemogenic promoters.","method":"VP16/engrailed fusion proteins, retroviral transformation, chromatin immunoprecipitation (ChIP) on Flt3 promoter","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP demonstrating direct promoter occupancy combined with structure-function gain-of-function analysis","pmids":["16648484"],"is_preprint":false},{"year":2007,"finding":"Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential; knockout, knockdown, and dominant-negative approaches show that MLL transformation requires Meis1 and is co-dependent on redundant contributions of Pbx2 and Pbx3. Meis1 quantitatively controls self-renewal extent, differentiation arrest, cycling, and in vivo LSC generation rate.","method":"Conditional knockout, shRNA knockdown, dominant-negative genetic approaches, in vivo LSC frequency assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal loss-of-function methods with quantitative LSC readouts","pmids":["17942707"],"is_preprint":false},{"year":2008,"finding":"Meis1 directly occupies regulatory sequences of Trib2, Flt3, Dlk1, Ccl3, Ccl4, Pf4, and Rgs1 as shown by ChIP; the PBX-interaction domain, homeodomain, and C-terminal domain are all required for Meis1 leukemogenic collaboration with NUP98-HOXD13, while the N-terminal domain is required for Flt3 upregulation but dispensable for leukemia, indicating Flt3-independent leukemogenic pathways.","method":"ChIP, structure-function deletion analysis, murine bone marrow transplantation, gene expression profiling","journal":"Experimental hematology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP for direct target occupancy plus structure-function analysis in vivo","pmids":["18375036"],"is_preprint":false},{"year":2009,"finding":"Meis1 regulates proximodistal patterning of the mouse limb in a Pbx1-independent manner; Msx2:Meis1 transgenic mice display altered P-D patterning and shifted Hox gene expression domains similar to chick, but Pbx1 deficiency does not modify this phenotype, suggesting Pbx1 is dispensable or another Pbx paralog provides the Meis1 partner function in this context.","method":"Transgenic mouse overexpression (Msx2 promoter-driven Meis1), Pbx1 knockout cross, limb Hox gene expression analysis","journal":"The International journal of developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic approach; single lab but multiple transgenic/KO combinations","pmids":["19247936"],"is_preprint":false},{"year":2009,"finding":"HOXA9 modulates Meis1 expression indirectly through upregulation of CREB1 and PKNOX1: ChIP showed HOXA9 does not directly bind the Meis1 promoter, but HOXA9 directly activates CREB1 and PKNOX1 transcription, and forced CREB1 expression in Hoxa9-/- bone marrow restores Meis1 mRNA levels, identifying CREB1 as a mediator of HOXA9 regulation of Meis1.","method":"ChIP, gene expression analysis in Hoxa9-/- mice, retroviral CREB1 overexpression rescue experiment","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP ruling out direct binding plus genetic rescue experiment identifying indirect pathway","pmids":["19620287"],"is_preprint":false},{"year":2010,"finding":"GSK-3 promotes conditional association of CREB and its coactivators TORC and CBP with MEIS1 to facilitate HOX-mediated transcription and transformation in MLL leukemia; this mechanism is required for maintenance of the MLL leukemia stem cell transcriptional program and applies broadly to HOX-associated leukemias.","method":"Co-immunoprecipitation of CREB/TORC/CBP with MEIS1, GSK-3 inhibition, reporter gene assays, leukemia transformation assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP establishing protein complex, functional validation with inhibitor and transformation assay","pmids":["20541704"],"is_preprint":false},{"year":2010,"finding":"Meis1 directly activates cyclin D3 transcription; a transcriptional repressor form (M33-Meis1) blocks G1-to-S phase progression by reducing cyclin D3 levels and inhibiting Rb hyperphosphorylation; overexpression of cyclin D3 partially rescues M33-Meis1-induced growth suppression, linking Meis1 growth-promoting activity to the cyclin D-Rb cell cycle axis.","method":"ChIP identifying cyclin D3 as direct target, M33-Meis1 repressor fusion, cell cycle analysis, Rb phosphorylation assay, cyclin D3 rescue experiment","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP plus mechanistic rescue experiment defining downstream pathway","pmids":["20237320"],"is_preprint":false},{"year":2010,"finding":"Meis1 and Pbx act upstream of gata1 in the erythropoietic transcription factor hierarchy in zebrafish; morpholino knockdown of Meis1 and Pbx causes severe reduction in gata1 expression and failure to produce circulating erythrocytes with increased myeloid cells; gata1 overexpression rescues hemoglobin expression in Pbx/Meis1-depleted embryos.","method":"Morpholino knockdown in zebrafish, genetic rescue by gata1 mRNA injection, in situ hybridization","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with morpholino knockdown and mRNA rescue; clean pathway placement","pmids":["20123093"],"is_preprint":false},{"year":2010,"finding":"ELF1, an ETS transcription factor, directly binds a conserved site 289 bp upstream of the human MEIS1 transcription start site and is required for MEIS1 promoter activity; ELF1 ChIP confirms enrichment at the MEIS1 promoter in MEIS1-expressing cells, and siRNA knockdown of ELF1 reduces MEIS1 expression.","method":"Phylogenetic sequence analysis, promoter reporter assay with truncation/mutation, EMSA, ChIP, siRNA knockdown","journal":"Experimental hematology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP plus mutagenesis plus functional reporter plus knockdown phenotype","pmids":["20600580"],"is_preprint":false},{"year":2011,"finding":"MN1-induced leukemogenesis requires the MEIS1/AbdB-like HOX-protein complex; ChIP-seq shows extensive overlap of MN1 and MEIS1 chromatin binding sites; common myeloid progenitors (CMP) but not granulocyte-macrophage progenitors (GMP) can be transformed by MN1, and complementation of GMP with MEIS1/AbdB-like HOX genes restores susceptibility, demonstrating cell-of-origin susceptibility is determined by MEIS1/HOX expression.","method":"ChIP-seq, complementation assay in primary bone marrow cells, in vivo leukemia transplantation","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP-seq plus genetic complementation with in vivo validation","pmids":["21741595"],"is_preprint":false},{"year":2013,"finding":"Meis1 is a critical transcriptional regulator of cardiomyocyte cell cycle arrest; cardiomyocyte-specific Meis1 deletion extends the postnatal proliferative window and reactivates cardiomyocyte mitosis in adult heart without deleterious cardiac function effects; Meis1 overexpression decreases neonatal myocyte proliferation and inhibits neonatal heart regeneration. Meis1 is required for transcriptional activation of CDK inhibitors p15, p16, and p21.","method":"Cardiomyocyte-specific conditional knockout, Meis1 overexpression in neonatal heart, cardiomyocyte mitosis assay, cardiac function assessment, target gene expression analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO and OE with multiple phenotypic readouts plus downstream target identification; replicated subsequently","pmids":["23594737"],"is_preprint":false},{"year":2014,"finding":"PREP1 and MEIS1 competitively heterodimerize with PBX1 in mouse embryonic fibroblasts; MEIS1 alone transforms Prep1-deficient fibroblasts; PREP1 overexpression inhibits MEIS1 tumorigenicity by sequestering PBX1, which destabilizes MEIS1 protein post-translationally. MEIS1 interaction with DDX3X and DDX5 (identified by Prep1-competition reducing these interactions) is essential for MEIS1-driven tumorigenesis.","method":"Co-immunoprecipitation, transformation assay in MEFs, protein stability assay, transcriptomic analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, competitive binding, protein stability with functional transformation readout","pmids":["24578510"],"is_preprint":false},{"year":2014,"finding":"Conditional Meis1 knockout in adult hematopoietic cells causes significant reduction in hematopoietic stem/progenitor cells due to impaired self-renewal and reduced quiescence in a cell-autonomous manner, resulting in stem cell exhaustion. Meis1 deficiency downregulates Pbx1-dependent HSC signature genes, indicating functional cooperation with Pbx1 in HSC maintenance.","method":"Conditional knockout in adult mice (tamoxifen-inducible), FACS enumeration of HSPCs, competitive transplantation, BrdU quiescence assay, gene expression profiling","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with multiple functional readouts and mechanistic gene expression data","pmids":["24498346"],"is_preprint":false},{"year":2014,"finding":"C/EBPα is a critical collaborator required for Hoxa9/Meis1-mediated leukemogenesis; over 50% of Hoxa9 genome-wide binding sites are co-bound by C/EBPα; Hoxa9 represses the Cdkn2a/b locus in concert with C/EBPα to overcome G1 cell cycle arrest; C/EBPα loss greatly improves survival in Hoxa9/Meis1-induced leukemia models.","method":"ChIP-seq, in vitro transformation assay, murine leukemia model, loss-of-function genetic approach","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide ChIP-seq showing co-occupancy plus genetic loss-of-function with in vivo survival readout","pmids":["24958854"],"is_preprint":false},{"year":2014,"finding":"An RLS-associated intronic SNP (rs12469063) in MEIS1 reduces enhancer activity in the ganglionic eminences of the developing mouse forebrain; CREB1 binds this enhancer and the risk SNP affects CREB1 binding in vitro; heterozygous Meis1-deficient mice exhibit circadian hyperactivity resembling RLS phenotype.","method":"Zebrafish and mouse enhancer reporter assays, EMSA for CREB1 binding with allelic variants, heterozygous Meis1 KO behavioral phenotyping","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo enhancer activity assay with allele dependence, in vitro binding assay with mutagenesis, and mouse model phenotype","pmids":["24642863"],"is_preprint":false},{"year":2015,"finding":"Pbx3 and Meis1 must dimerize to support Hox-induced leukemia; in the absence of Pbx3, Meis1 is rapidly ubiquitinated and degraded via the proteasome. The Meis1 Pbx-binding domain is required to prevent ubiquitination; Pbx3 binding stabilizes Meis1. Additionally, Pbx3 overexpression induces endogenous Meis1 transcription. Meis1/Pbx3 dimerization is required for high-affinity DNA/Hoxa9/Meis1/Pbx3 complex formation in vitro.","method":"Deletion analysis, protein half-life assay, proteasome inhibition, in vitro EMSA for quaternary complex, murine leukemia transplantation","journal":"Haematologica","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic dissection of protein stability via ubiquitination, in vitro complex reconstitution, in vivo validation","pmids":["25911551"],"is_preprint":false},{"year":2015,"finding":"PBX3 and MEIS1 co-expression, without a HOX gene, is sufficient to transform normal mouse hematopoietic stem/progenitor cells and cause AML in vivo, recapitulating the MLL-fusion core transcriptome including endogenous Hoxa gene upregulation; disruption of MEIS1-PBX3 binding abolishes transformation and HOX gene upregulation.","method":"Retroviral co-expression in primary mouse HSPC, in vitro transformation assay, in vivo transplantation AML model, gene expression profiling, interaction-disrupting mutants","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including in vivo leukemia and interaction-disruption mutants","pmids":["26747896"],"is_preprint":false},{"year":2015,"finding":"MEIS1 binds an upstream sequence of Pax6 to enhance its transcription in cerebellar granule cell precursors; this Meis1-Pax6 cascade upregulates Smad proteins to enhance BMP signaling, leading to Atoh1 protein degradation in the inner EGL and promoting GCP-to-GC differentiation. Conditional Meis1 KO in the GC lineage causes smaller cerebella with disorganized lobules and ectopic Atoh1-positive GCPs.","method":"Conditional cerebellar KO, ChIP for Pax6 upstream sequence, in vitro promoter assay, Smad/BMP pathway analysis, Atoh1 expression analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP identifying direct target plus conditional KO with pathway dissection","pmids":["29317485"],"is_preprint":false},{"year":2015,"finding":"Sequential and mutually exclusive binding of MEIS1 and NKX2-5 to overlapping sites on the Popdc2 cardiac gene enhancer provides a mechanism for spatiotemporal regulation: as cardiac progenitors differentiate, they sequentially experience high MEIS1 then increasing NKX2-5, whose binding displaces MEIS1 from shared target sites to switch transcriptional output.","method":"ChIP, reporter assays, in vitro binding competition assay, expression profiling during cardiac differentiation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP plus in vitro competition assay establishing mutually exclusive binding mechanism","pmids":["26411676"],"is_preprint":false},{"year":2015,"finding":"Meis1 regulates a HLF-oxidative stress axis in MLL leukemia: Meis1 loss leads to increased oxidative stress, oxygen flux, and apoptosis in leukemic cells; ChIP and gene expression studies identify HLF as a direct Meis1 target gene; hypoxia or HLF expression rescues leukemia development in Meis1-deficient cells.","method":"Inducible Meis1-knockout crossed with MLL-AF9 knockin mice, ChIP for HLF promoter, oxidative stress measurement, HLF rescue experiment","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP identifying direct target plus genetic rescue demonstrating mechanistic pathway","pmids":["25740828"],"is_preprint":false},{"year":2015,"finding":"MEIS1 promoter is hypomethylated and transcriptionally reactivated in DNMT3A-mutant AML patients; whole-genome bisulfite sequencing and DNA methylation microarrays identify MEIS1 as the key gene undergoing promoter hypomethylation-associated reactivation, providing an alternative (MLL-fusion-independent) mechanism for engaging MEIS1-dependent oncogenic transcription.","method":"Whole-genome bisulfite sequencing, DNA methylation microarrays in patient samples","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide bisulfite sequencing with patient samples; single study linking DNMT3A mutation to MEIS1 epigenetic reactivation","pmids":["26434589"],"is_preprint":false},{"year":2016,"finding":"MEIS1 promotes leukemic cell homing and engraftment in bone marrow through transactivation of synaptotagmin-like 1 (SYTL1/SLP1); ChIP in leukemic cells shows MEIS1 directly binds the SYTL1 gene; SYTL1 replacement in MEIS1-deficient cells restores cell migration and engraftment; SYTL1 activates CXCL12/CXCR4 signaling by regulating intracellular trafficking of CXCR4.","method":"ChIP for SYTL1 promoter, MEIS1 deficiency murine model, SYTL1 rescue experiment, CXCR4 trafficking assay, migration assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP identifying direct target plus genetic rescue plus receptor trafficking mechanistic readout","pmids":["27018596"],"is_preprint":false},{"year":2017,"finding":"Hoxa9 and Meis1 cooperatively suppress miR-146a to upregulate Syk expression and activity in AML; Meis1 regulates Syk indirectly through PU.1-dependent regulation of miR-146a, which directly targets Syk; Syk signaling in turn induces Meis1 in the context of Hoxa9, creating a regulatory feedback loop; Syk inhibition disrupts this loop and prolongs survival of Hoxa9/Meis1 AML mice.","method":"(Phospho)proteomic analysis, miR-146a target validation for Syk, ChIP/reporter assays for PU.1-miR-146a axis, Syk inhibitor treatment in murine AML model","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1-2 — proteomics plus miRNA target validation plus in vivo pharmacologic target validation","pmids":["28399410"],"is_preprint":false},{"year":2018,"finding":"PPM1K (a mitochondrial Ser/Thr phosphatase promoting BCAA catabolism) maintains MEIS1 and p21 protein levels by decreasing CDC20-mediated ubiquitination and degradation; PPM1K deficiency reduces MEIS1/p21 signaling, impairs HSC glycolysis and quiescence, and decreases repopulation; PPM1K deletion also extends survival in a murine leukemia model.","method":"Genetically encoded BCAA fluorescent sensor, conditional KO, ubiquitination assay, HSC functional assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — ubiquitination mechanistic assay plus conditional KO with multiple functional readouts","pmids":["29719258"],"is_preprint":false},{"year":2018,"finding":"MEIS1 controls human hematopoiesis from pluripotent stem cells in a stage-specific manner: it is required for specification of APLNR+ mesoderm progenitors to functional hemogenic endothelial progenitors (via TAL1 as downstream mediator), and is separately required for megakaryopoiesis/thrombopoiesis (via FLI1 as downstream target); mechanistic ChIP or promoter binding for TAL1 and FLI1 within this context was demonstrated.","method":"hPSC differentiation, MEIS1 overexpression/knockdown, ChIP for TAL1 and FLI1, functional hematopoietic assays","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP identifying direct targets plus stage-specific functional dissection in human stem cell model","pmids":["29358086"],"is_preprint":false},{"year":2018,"finding":"MEIS1 directly binds two specific sites in the SKOR1 promoter to positively regulate SKOR1 expression; an RLS-associated SNP in the SKOR1 promoter region modifies MEIS1-driven activation, directly linking two GWAS-identified RLS genes through a transcriptional regulatory relationship.","method":"MEIS1 ChIP at SKOR1 promoter sites, promoter reporter assay with site mutagenesis, allele-specific reporter assay with RLS SNP","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP plus mutagenesis of binding sites plus allele-specific functional assay","pmids":["30111810"],"is_preprint":false},{"year":2018,"finding":"MEIS1 interacts directly with the androgen receptor (AR) protein; co-immunoprecipitation and GST pull-down confirm a protein-protein interaction; MEIS1 modulates AR cytoplasm/nucleus translocation, reduces AR recruitment to the PSA gene promoter androgen response element, and promotes recruitment of corepressors NCoR and SMRT in the presence of androgen, acting as a novel AR co-repressor.","method":"Co-immunoprecipitation, GST pull-down, nuclear fractionation, ChIP for AR at PSA promoter, reporter assay","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal pulldown plus ChIP plus functional localization assay","pmids":["25158280"],"is_preprint":false},{"year":2019,"finding":"MEIS1 suppression in fetal cardiomyocytes (siRNA) increases maximal oxygen consumption and mitochondrial activity while decreasing expression of glycolytic genes, demonstrating that MEIS1 actively suppresses oxidative phosphorylation and promotes glycolysis in the developing cardiomyocyte; the normal developmental downregulation of MEIS1 around birth underlies the perinatal metabolic switch.","method":"siRNA knockdown in primary fetal sheep cardiomyocytes, Seahorse metabolic flux analysis, MitoTracker staining, gene expression analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with direct metabolic readout (Seahorse) in primary cells","pmids":["30884246"],"is_preprint":false},{"year":2016,"finding":"Meis1 inactivation in mouse neural crest leads to altered sympatho-vagal cardiac regulation and increased susceptibility to sudden cardiac death; Meis1-deficient sympathetic neurons die by apoptosis from embryonic to perinatal stages; Meis1 regulates transcription of key molecules for the endosomal machinery, and Rab5+ endosome trafficking is severely altered in Meis1-inactivated sympathetic neurons.","method":"Neural crest-specific conditional Meis1 knockout, cardiac electrophysiology, sympathetic neuron survival assay, endosome trafficking analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific conditional KO with multiple mechanistic cellular readouts","pmids":["26857994"],"is_preprint":false},{"year":2013,"finding":"Gfi1b directly represses Meis1 transcription in the erythroid lineage but not in megakaryocytes; Gfi1b and its cofactors LSD1 and CoREST occupy distinct regions of the Meis1 promoter in erythroid cells; LSD1 inhibition upregulates Meis1 specifically in erythroid cells; the repression requires the Gfi1b SNAG domain and DNA binding domain as shown by transfection of mutant forms.","method":"ChIP for Gfi1b/LSD1/CoREST at Meis1 promoter, LSD1 inhibitor treatment, gfi1b knockout fetal liver, promoter reporter assay with Gfi1b mutants","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP plus mutagenesis of repressor domain plus KO and inhibitor phenotype","pmids":["23308270"],"is_preprint":false},{"year":2022,"finding":"MEIS1 transcription is epigenetically suppressed in colorectal cancer by EZH2-DNMT3a recruited by lncRNA ELFN1-AS1 to the MEIS1 promoter; MEIS1 suppression drives oxaliplatin resistance through enhanced FEN1 expression; EZH2 inhibitor GSK126 or ELFN1-AS1 ASO restores MEIS1 expression and reverses resistance.","method":"lncRNA-protein complex analysis, ChIP for EZH2/DNMT3a at MEIS1 promoter, FEN1 expression assay, in vivo tumor xenograft, drug resistance assay","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP demonstrating epigenetic complex at MEIS1 promoter plus in vitro and in vivo functional validation","pmids":["35351858"],"is_preprint":false}],"current_model":"MEIS1 is a TALE-class homeodomain transcription factor that functions primarily as a nuclear transcriptional regulator by forming cooperative DNA-binding complexes with PBX family proteins and AbdB-like HOX proteins (notably HOXA9), regulating target genes including p15/p16/p21 (cell cycle arrest in cardiomyocytes), FLT3/CD34 (HSC and leukemia stem cell identity), cyclin D3 and HLF (cell cycle and metabolic control), SYTL1 (bone marrow homing via CXCR4 trafficking), TAL1/FLI1 (hemogenic endothelium and megakaryopoiesis), and SKOR1 (neural development linked to RLS); PBX binding stabilizes MEIS1 protein against CDC20/ubiquitin-proteasome-mediated degradation; GSK-3 promotes CREB/CBP/TORC co-activator assembly on MEIS1 to drive HOX-dependent transcription; ELF1 directly activates MEIS1 transcription, while Gfi1b/LSD1/CoREST repress it in erythroid cells and EZH2/DNMT3a repress it epigenetically in cancer; MEIS1 is rate-limiting for MLL-fusion leukemia stem cell self-renewal and is required for definitive hematopoiesis, megakaryocyte production, angiogenesis, sympathetic neuron survival, cardiomyocyte cell cycle arrest, cerebellar granule cell differentiation, and proximodistal limb patterning."},"narrative":{"teleology":[{"year":1995,"claim":"Identification of MEIS1 as a TALE-class homeobox gene at a retroviral insertion site in myeloid leukemia established it as a candidate oncogene and founding member of a new homeodomain subfamily.","evidence":"cDNA cloning, Northern blot, and retroviral insertional mutagenesis in BXH-2 mice","pmids":["7565694"],"confidence":"High","gaps":["No DNA-binding specificity or partner proteins yet identified","Mechanism of leukemogenic activation unknown"]},{"year":1997,"claim":"Demonstration that MEIS1 forms cooperative DNA-binding heterodimers with both AbdB-like HOX proteins and PBX1 via distinct interaction interfaces defined the two-partner binding logic that underlies all subsequent MEIS1 function.","evidence":"EMSA with purified proteins, cooperative binding kinetics, deletion mapping distinguishing PBX- vs HOX-interaction domains","pmids":["9343407","9405651"],"confidence":"High","gaps":["No trimeric complex yet demonstrated","In vivo relevance of these interactions not established"]},{"year":1999,"claim":"Reconstitution of a trimeric HOXA9–PBX2–MEIS1 complex in myeloid nuclei and demonstration that MEIS1/Hth drives PBX/EXD nuclear import established the core transcriptional unit and explained how MEIS1 controls partner activity in vivo.","evidence":"Co-IP from myeloid nuclear extracts, EMSA for trimeric complex, Drosophila hth genetic epistasis, chick limb ectopic expression","pmids":["10082572","9463350","10586884"],"confidence":"High","gaps":["Genome-wide target genes unknown","Relative contribution of PBX nuclear import vs direct transcriptional activation not resolved"]},{"year":2001,"claim":"Showing that PREP1 cannot substitute for MEIS1 in HOXA9-induced AML despite shared PBX-binding ability revealed that MEIS1 leukemogenic function extends beyond PBX nuclear retention to include unique transactivation or target-gene selection.","evidence":"Retroviral co-expression and bone marrow transplantation leukemia model","pmids":["11113197"],"confidence":"High","gaps":["Unique MEIS1 domains responsible for leukemogenic specificity not mapped","Direct transcriptional targets in leukemia unknown"]},{"year":2004,"claim":"Germline Meis1 knockout and identification of Meis1 as a critical downstream effector of MLL-ENL together established MEIS1 as essential for definitive hematopoiesis, megakaryopoiesis, angiogenesis, and HSC function, and as a key mediator of MLL-fusion leukemogenesis.","evidence":"Meis1-/- mouse embryonic lethality with hemorrhage and HSC failure; inducible MLL-ENL system showing Hoxa9+Meis1 substitutes for MLL-ENL","pmids":["14713950","14701735"],"confidence":"High","gaps":["Cell-autonomous vs non-cell-autonomous contributions not fully separated","Direct MEIS1 target genes in HSCs not yet identified"]},{"year":2005,"claim":"Structure–function analysis showed that MEIS1 programs leukemia stem cell identity through PBX-dependent induction of HSC genes (FLT3, CD34), requiring PBX binding, DNA binding, and a C-terminal transactivation domain.","evidence":"Domain deletion mutants in retroviral transformation and leukemia transplantation assays","pmids":["15755900"],"confidence":"High","gaps":["Whether FLT3 alone is sufficient for MEIS1 leukemogenic effect unclear","Structural basis of C-terminal domain function unknown"]},{"year":2006,"claim":"ChIP demonstration that MEIS1 and HOXA9 co-occupy the FLT3 promoter, combined with VP16-Meis1 acting as an autonomous oncogene that activates endogenous HOX genes, proved direct promoter co-occupancy and revealed bidirectional HOX-MEIS1 regulatory feedback.","evidence":"VP16/engrailed fusion proteins, ChIP on Flt3 promoter, retroviral transformation assays","pmids":["16648484"],"confidence":"High","gaps":["Genome-wide co-occupancy maps not yet available","Mechanism of endogenous HOX activation by VP16-Meis1 not defined"]},{"year":2007,"claim":"Multiple loss-of-function approaches established MEIS1 as the rate-limiting factor for MLL leukemia stem cell self-renewal, quantitatively controlling LSC frequency, and identified Pbx2/Pbx3 redundancy as the PBX partner requirement.","evidence":"Conditional knockout, shRNA, dominant-negative in MLL-transformed cells with in vivo LSC frequency assay","pmids":["17942707"],"confidence":"High","gaps":["Specific MEIS1 target genes mediating self-renewal vs differentiation arrest not separated","Whether MEIS1 is druggable in this context unknown"]},{"year":2010,"claim":"Discovery that GSK-3 promotes CREB/TORC/CBP coactivator assembly on MEIS1 provided the first cofactor-recruitment mechanism for MEIS1 transcriptional activation in HOX-dependent leukemia, while identification of cyclin D3 as a direct target linked MEIS1 to the cell cycle machinery.","evidence":"Co-IP of CREB/TORC/CBP with MEIS1, GSK-3 inhibition, ChIP identifying cyclin D3, M33-Meis1 repressor with rescue","pmids":["20541704","20237320"],"confidence":"High","gaps":["How GSK-3 kinase activity mechanistically promotes coactivator assembly on MEIS1 not resolved at molecular level","Whether cyclin D3 is required for leukemia in vivo not tested"]},{"year":2011,"claim":"ChIP-seq revealed extensive genome-wide co-occupancy of MN1 and MEIS1 and showed that cell-of-origin susceptibility to MN1 leukemia is determined by MEIS1/HOX expression levels, establishing MEIS1 as a gatekeeper of oncogenic competence.","evidence":"ChIP-seq, genetic complementation of GMP with MEIS1/AbdB-HOX, in vivo transplantation","pmids":["21741595"],"confidence":"High","gaps":["Whether MN1 and MEIS1 physically interact or just co-bind DNA not determined","Full set of co-regulated target genes not defined"]},{"year":2013,"claim":"Cardiomyocyte-specific Meis1 deletion extended postnatal proliferation and reactivated adult cardiomyocyte mitosis, while Gfi1b/LSD1/CoREST were shown to repress Meis1 in erythroid cells, revealing MEIS1 as a master regulator of cell-cycle exit and demonstrating lineage-specific epigenetic control of MEIS1 itself.","evidence":"Cardiomyocyte-specific conditional KO and OE with mitosis and cardiac function readouts; ChIP for Gfi1b/LSD1/CoREST at Meis1 promoter in erythroid cells","pmids":["23594737","23308270"],"confidence":"High","gaps":["Whether MEIS1 deletion enables functional cardiac regeneration after injury not shown","Gfi1b repression mechanism limited to erythroid lineage"]},{"year":2014,"claim":"Conditional adult Meis1 KO showed HSC exhaustion due to impaired quiescence and self-renewal, PREP1 was found to antagonize MEIS1 by competing for PBX binding and destabilizing MEIS1 protein, and an RLS-associated SNP was shown to reduce MEIS1 enhancer activity via impaired CREB1 binding, broadening MEIS1 biology to stem cell homeostasis and neurological disease.","evidence":"Adult conditional KO with FACS/transplantation; PREP1 competition assays with protein stability readout; enhancer reporter assays with allelic variants and Meis1+/- behavioral phenotyping","pmids":["24498346","24578510","24642863"],"confidence":"High","gaps":["Mechanism by which MEIS1 haploinsufficiency produces RLS-like behavior not molecularly defined","Identity of DDX3X/DDX5 functional role in MEIS1 tumorigenesis not elaborated"]},{"year":2015,"claim":"PBX3 binding was shown to stabilize MEIS1 by preventing ubiquitin-proteasome degradation, PBX3–MEIS1 co-expression alone was sufficient for AML, and MEIS1 was found to regulate a HLF-oxidative-stress axis and SYTL1-CXCR4 trafficking in leukemia, defining protein stability control and multiple downstream effector pathways.","evidence":"Ubiquitination assays with proteasome inhibition; PBX3+MEIS1 co-expression leukemia model; ChIP for HLF and SYTL1; oxidative stress and migration rescue experiments","pmids":["25911551","26747896","25740828","27018596"],"confidence":"High","gaps":["E3 ligase responsible for MEIS1 ubiquitination not identified (CDC20 link came later)","Whether HLF and SYTL1 pathways are independent or convergent unknown"]},{"year":2016,"claim":"Neural crest-specific Meis1 knockout revealed a requirement for sympathetic neuron survival and endosomal trafficking regulation, linking MEIS1 to Rab5+ endosome function and cardiac autonomic control including susceptibility to sudden cardiac death.","evidence":"Neural crest-specific conditional KO, sympathetic neuron apoptosis assay, Rab5 endosome trafficking analysis, cardiac electrophysiology","pmids":["26857994"],"confidence":"High","gaps":["Direct transcriptional targets mediating endosomal machinery regulation not fully identified","Whether this mechanism operates in other neuronal populations unknown"]},{"year":2018,"claim":"Multiple studies defined new MEIS1 transcriptional targets and regulatory axes: PPM1K was shown to maintain MEIS1 protein by opposing CDC20-mediated ubiquitination in HSCs; MEIS1 was found to drive hemogenic endothelium specification via TAL1 and megakaryopoiesis via FLI1; MEIS1 directly activates SKOR1 at an RLS SNP-modifiable promoter; and MEIS1 acts as an AR corepressor recruiting NCoR/SMRT.","evidence":"CDC20 ubiquitination assays, PPM1K conditional KO; hPSC differentiation with ChIP for TAL1/FLI1; SKOR1 promoter ChIP and allele-specific reporter; AR co-IP, GST pulldown, ChIP at PSA promoter","pmids":["29719258","29358086","30111810","25158280"],"confidence":"High","gaps":["PPM1K–CDC20–MEIS1 axis not confirmed in leukemia context","AR corepressor function studied in prostate cancer cells only","SKOR1 regulation link to RLS pathophysiology not mechanistically complete"]},{"year":2019,"claim":"Metabolic flux analysis in cardiomyocytes demonstrated that MEIS1 actively suppresses oxidative phosphorylation and promotes glycolysis, establishing the mechanistic basis for the perinatal metabolic switch accompanying cardiomyocyte cell-cycle arrest.","evidence":"siRNA knockdown in primary fetal cardiomyocytes with Seahorse metabolic flux analysis","pmids":["30884246"],"confidence":"High","gaps":["Direct transcriptional targets mediating metabolic reprogramming not identified","Whether metabolic shift is separable from cell-cycle arrest not tested"]},{"year":2022,"claim":"Epigenetic silencing of MEIS1 by EZH2–DNMT3a recruited by lncRNA ELFN1-AS1 was shown to drive oxaliplatin resistance in colorectal cancer through FEN1 upregulation, revealing an MLL-independent mechanism of MEIS1 suppression with therapeutic implications.","evidence":"ChIP for EZH2/DNMT3a at MEIS1 promoter, lncRNA–protein interaction assays, FEN1 expression, xenograft drug resistance model","pmids":["35351858"],"confidence":"High","gaps":["Whether MEIS1 directly represses FEN1 or acts indirectly not resolved","Generalizability to other cancer types not established"]},{"year":null,"claim":"A high-resolution structural model of the MEIS1–PBX–HOX trimeric complex on DNA, the full catalog of direct MEIS1 genomic targets across normal tissues, and the mechanism by which MEIS1 haploinsufficiency causes restless legs syndrome-related neuronal phenotypes remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of MEIS1-containing trimeric complex","Genome-wide MEIS1 target maps in non-leukemic tissues largely absent","Neuronal cell types and circuits through which MEIS1 contributes to RLS not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,2,3,6,9,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[12,13,19,23,30,32,34,37,38]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5,6]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,12,13,19,21,23,30,32,37,38,42]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,10,16,30,41]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[19,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,25,37]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,11,14,22,29,33,43]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[42,43]}],"complexes":["MEIS1-PBX heterodimer","MEIS1-PBX-HOXA9 trimer","MEIS1-CREB-CBP-TORC coactivator complex"],"partners":["PBX1","PBX2","PBX3","HOXA9","CREB1","CBP","DDX3X","AR"],"other_free_text":[]},"mechanistic_narrative":"MEIS1 is a TALE-class homeodomain transcription factor that orchestrates cell fate decisions across hematopoiesis, cardiac development, limb patterning, and neural differentiation by forming cooperative DNA-binding complexes with PBX and HOX family proteins. MEIS1 heterodimerizes with PBX proteins through a conserved N-terminal domain distinct from the HOX-interaction interface, and assembles trimeric MEIS1–PBX–HOXA9 complexes on composite DNA elements to activate target genes including FLT3, cyclin D3, HLF, SYTL1, TAL1, FLI1, PAX6, and SKOR1; GSK-3 promotes recruitment of CREB/CBP/TORC coactivators to MEIS1, and PBX binding stabilizes MEIS1 protein by preventing CDC20-mediated ubiquitin–proteasome degradation [PMID:9343407, PMID:10082572, PMID:20541704, PMID:29719258]. MEIS1 is essential for definitive hematopoiesis, megakaryopoiesis, and HSC quiescence; its deletion causes embryonic lethality with hemorrhage and vascular defects, while in adult HSCs it maintains self-renewal and glycolytic metabolism [PMID:14713950, PMID:24498346, PMID:30884246]. MEIS1 is a rate-limiting driver of MLL-fusion leukemia stem cell self-renewal and independently controls cardiomyocyte cell-cycle arrest through activation of p15/p16/p21, sympathetic neuron survival via endosomal trafficking, cerebellar granule cell differentiation via PAX6–BMP signaling, and proximodistal limb patterning [PMID:17942707, PMID:23594737, PMID:26857994, PMID:29317485, PMID:10586884]."},"prefetch_data":{"uniprot":{"accession":"O00470","full_name":"Homeobox protein Meis1","aliases":[],"length_aa":390,"mass_kda":43.0,"function":"Acts as a transcriptional regulator of PAX6. Acts as a transcriptional activator of PF4 in complex with PBX1 or PBX2. Required for hematopoiesis, megakaryocyte lineage development and vascular patterning. May function as a cofactor for HOXA7 and HOXA9 in the induction of myeloid leukemias","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O00470/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MEIS1","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MEIS1","total_profiled":1310},"omim":[{"mim_id":"619443","title":"MEIS HOMEOBOX 3; MEIS3","url":"https://www.omim.org/entry/619443"},{"mim_id":"618774","title":"CEBALID SYNDROME; CEBALID","url":"https://www.omim.org/entry/618774"},{"mim_id":"612853","title":"RESTLESS LEGS SYNDROME, SUSCEPTIBILITY TO, 7; RLS7","url":"https://www.omim.org/entry/612853"},{"mim_id":"611185","title":"RESTLESS LEGS SYNDROME, SUSCEPTIBILITY TO, 6; RLS6","url":"https://www.omim.org/entry/611185"},{"mim_id":"607108","title":"PAIRED BOX GENE 6; PAX6","url":"https://www.omim.org/entry/607108"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MEIS1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O00470","domains":[{"cath_id":"1.10.10.60","chopping":"280-339","consensus_level":"high","plddt":93.0375,"start":280,"end":339},{"cath_id":"1.20.58","chopping":"68-178","consensus_level":"high","plddt":83.5297,"start":68,"end":178}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00470","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00470-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00470-F1-predicted_aligned_error_v6.png","plddt_mean":65.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MEIS1","jax_strain_url":"https://www.jax.org/strain/search?query=MEIS1"},"sequence":{"accession":"O00470","fasta_url":"https://rest.uniprot.org/uniprotkb/O00470.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00470/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00470"}},"corpus_meta":[{"pmid":"23594737","id":"PMC_23594737","title":"Meis1 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The interaction interface on MEIS1 is distinct from the tryptophan motif used by HOX proteins.\",\n      \"method\": \"EMSA, cooperative DNA-binding assays, deletion mapping, comparison with E2a-PBX1\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding reconstitution with domain mapping; replicated by multiple labs\",\n      \"pmids\": [\"9405651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MEIS1 cooperatively binds the cAMP-responsive sequence CRS1 of bovine CYP17 together with PBX1; neither protein binds alone. Mutagenesis shows a dedicated MEIS1 binding site adjacent to the PBX site, and the conserved tryptophan N-terminal to the MEIS1 homeodomain is NOT required for Pbx cooperative binding, distinguishing the PBX-MEIS1 interaction from the PBX-HOX interaction. The interaction is evolutionarily conserved with Drosophila extradenticle and C. elegans ceh-20.\",\n      \"method\": \"CRS1 affinity chromatography purification of MEIS1 from adrenal cell extracts, EMSA, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis; identifies specific binding site and mechanism\",\n      \"pmids\": [\"9525891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Homothorax (hth), the Drosophila orthologue of MEIS1, is required for nuclear localization of Extradenticle (EXD, orthologue of PBX); ectopic HTH drives ectopic nuclear EXD. In hth mutants, EXD protein remains cytoplasmic; in exd mutants, HTH protein levels are severely reduced, establishing a mutual dependency.\",\n      \"method\": \"Genetic epistasis in Drosophila, immunostaining, ectopic expression experiments\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic epistasis with protein localization readout; established mechanism conserved to vertebrates\",\n      \"pmids\": [\"9463350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MEIS1 promotes nuclear import of PBX1 in vertebrate limb cells; Meis1/2 expression is restricted to the proximal limb domain coinciding with nuclear PBX1; ectopic Meis1 in chicken limb or hth in Drosophila abolishes distal limb structures and causes distal-to-proximal identity transformations, demonstrating that restriction of Meis1/Hth to proximal regions is essential for proximodistal limb patterning.\",\n      \"method\": \"In situ hybridization, immunostaining, ectopic overexpression in chick and Drosophila, Drosophila genetics\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments tied to functional consequence; multiple organisms and orthogonal methods\",\n      \"pmids\": [\"10586884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HOXA9, PBX2, and MEIS1 form trimeric complexes in myeloid cell nuclei: MEIS1 enhances in vitro HOXA9-PBX protein complex formation in the absence of DNA and forms a trimeric EMSA complex on PBX-HOXA9 oligonucleotides. Immunoprecipitation of HOXA9 from myeloid cell extracts co-precipitates PBX2 and MEIS1. The three proteins co-localize in nuclear speckles.\",\n      \"method\": \"In vitro EMSA, co-immunoprecipitation from myeloid cell nuclear extracts, immunofluorescence co-localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of trimeric complex plus reciprocal co-IP from endogenous cell extracts\",\n      \"pmids\": [\"10082572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Pbx-Meis1/Prep1 heterodimers bind DNA cooperatively with myogenic bHLH transcription factors (MyoD, myogenin, Mrf-4, Myf-5) through a conserved tryptophan motif N-terminal to the bHLH DNA-binding domain; this tryptophan motif is required for MyoD to remodel chromatin at the Myogenin promoter and activate Myogenin transcription in vivo.\",\n      \"method\": \"EMSA, tryptophan motif mutagenesis, chromatin remodeling assay, transactivation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution plus mutagenesis with in vivo functional validation\",\n      \"pmids\": [\"10471746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MEIS1 genetically collaborates with both HOXA9 and HOXB3 to induce AML, but PREP1 overexpression cannot substitute for MEIS1 in HOXA9-induced AML despite shared ability to retain PBX in the nucleus, demonstrating that MEIS1 leukemogenic function extends beyond PBX nuclear retention.\",\n      \"method\": \"Murine bone marrow transplantation leukemia model, retroviral overexpression, genetic epistasis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis in primary cells/mice; replicated in subsequent studies\",\n      \"pmids\": [\"11113197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MEIS1, PBX1B, and PBX2 bind as MEIS1/PBX complexes to the TME (tandem repeat of MEIS1 binding element) in the platelet factor 4 (PF4) promoter to activate PF4 transcription in megakaryocytic cells; disruption of MEIS1 binding sites reduces promoter activity by approximately half in megakaryocytic HEL cells.\",\n      \"method\": \"EMSA, DNA affinity chromatography, Western blot, supershift assay, promoter reporter assay, dominant-negative inhibition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical purification of binding proteins, EMSA, mutagenesis of binding sites, functional reporter assay\",\n      \"pmids\": [\"12609849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Meis1-deficient mouse embryos die by E14.5 with failure to produce megakaryocytes, extensive hemorrhaging, lack of well-formed capillaries, and severely reduced colony-forming hematopoietic cells; Meis1-/- fetal liver cells fail to radioprotect irradiated mice and compete poorly in repopulation assays, establishing Meis1 as required for definitive hematopoiesis, megakaryocyte production, angiogenesis, and hematopoietic stem cell function.\",\n      \"method\": \"Germline knockout mouse, fetal liver transplantation, radioprotection assay, competitive repopulation, histology\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple specific phenotypic readouts; replicated in independent KO studies\",\n      \"pmids\": [\"14713950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Hoxa9 and Meis1 are key transcriptional targets upregulated by MLL-ENL; enforced co-expression of Hoxa9 with Meis1 is sufficient to substitute for MLL-ENL function and maintain continuous proliferation and differentiation arrest of hematopoietic cells.\",\n      \"method\": \"Inducible MLL-ENL-ERtm system, microarray expression profiling, retroviral co-expression, proliferation and differentiation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional MLL fusion system combined with gain-of-function reconstitution; replicated widely\",\n      \"pmids\": [\"14701735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Meis1 programs expression of FLT3 and CD34 (HSC-specific genes) in Hoxa9-immortalized myeloid progenitors, converting them to AML-initiating cells. Meis1 leukemogenic activity requires PBX binding, DNA binding, and a conserved C-terminal tail function. Meis1 establishes leukemia stem cell character through induction of HSC-associated genes.\",\n      \"method\": \"Retroviral transduction, in vitro progenitor culture, leukemia transplantation assay, domain deletion mutants\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — structure-function with multiple deletion mutants, in vivo leukemia assay, gene expression readout\",\n      \"pmids\": [\"15755900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A dominant transactivating VP16-Meis1 fusion acts as an autonomous oncogene without co-expressed HOX genes and all resulting leukemias show activation of endogenous Hoxa9/Hoxa7, indicating HOX gene activation is a key downstream event. ChIP confirmed co-occupancy of Hoxa9 and Meis1 on the Flt3 promoter, demonstrating Meis1-Pbx and Hox-Pbx complexes co-occupy leukemogenic promoters.\",\n      \"method\": \"VP16/engrailed fusion proteins, retroviral transformation, chromatin immunoprecipitation (ChIP) on Flt3 promoter\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP demonstrating direct promoter occupancy combined with structure-function gain-of-function analysis\",\n      \"pmids\": [\"16648484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential; knockout, knockdown, and dominant-negative approaches show that MLL transformation requires Meis1 and is co-dependent on redundant contributions of Pbx2 and Pbx3. Meis1 quantitatively controls self-renewal extent, differentiation arrest, cycling, and in vivo LSC generation rate.\",\n      \"method\": \"Conditional knockout, shRNA knockdown, dominant-negative genetic approaches, in vivo LSC frequency assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal loss-of-function methods with quantitative LSC readouts\",\n      \"pmids\": [\"17942707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Meis1 directly occupies regulatory sequences of Trib2, Flt3, Dlk1, Ccl3, Ccl4, Pf4, and Rgs1 as shown by ChIP; the PBX-interaction domain, homeodomain, and C-terminal domain are all required for Meis1 leukemogenic collaboration with NUP98-HOXD13, while the N-terminal domain is required for Flt3 upregulation but dispensable for leukemia, indicating Flt3-independent leukemogenic pathways.\",\n      \"method\": \"ChIP, structure-function deletion analysis, murine bone marrow transplantation, gene expression profiling\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP for direct target occupancy plus structure-function analysis in vivo\",\n      \"pmids\": [\"18375036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Meis1 regulates proximodistal patterning of the mouse limb in a Pbx1-independent manner; Msx2:Meis1 transgenic mice display altered P-D patterning and shifted Hox gene expression domains similar to chick, but Pbx1 deficiency does not modify this phenotype, suggesting Pbx1 is dispensable or another Pbx paralog provides the Meis1 partner function in this context.\",\n      \"method\": \"Transgenic mouse overexpression (Msx2 promoter-driven Meis1), Pbx1 knockout cross, limb Hox gene expression analysis\",\n      \"journal\": \"The International journal of developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic approach; single lab but multiple transgenic/KO combinations\",\n      \"pmids\": [\"19247936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HOXA9 modulates Meis1 expression indirectly through upregulation of CREB1 and PKNOX1: ChIP showed HOXA9 does not directly bind the Meis1 promoter, but HOXA9 directly activates CREB1 and PKNOX1 transcription, and forced CREB1 expression in Hoxa9-/- bone marrow restores Meis1 mRNA levels, identifying CREB1 as a mediator of HOXA9 regulation of Meis1.\",\n      \"method\": \"ChIP, gene expression analysis in Hoxa9-/- mice, retroviral CREB1 overexpression rescue experiment\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP ruling out direct binding plus genetic rescue experiment identifying indirect pathway\",\n      \"pmids\": [\"19620287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GSK-3 promotes conditional association of CREB and its coactivators TORC and CBP with MEIS1 to facilitate HOX-mediated transcription and transformation in MLL leukemia; this mechanism is required for maintenance of the MLL leukemia stem cell transcriptional program and applies broadly to HOX-associated leukemias.\",\n      \"method\": \"Co-immunoprecipitation of CREB/TORC/CBP with MEIS1, GSK-3 inhibition, reporter gene assays, leukemia transformation assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP establishing protein complex, functional validation with inhibitor and transformation assay\",\n      \"pmids\": [\"20541704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Meis1 directly activates cyclin D3 transcription; a transcriptional repressor form (M33-Meis1) blocks G1-to-S phase progression by reducing cyclin D3 levels and inhibiting Rb hyperphosphorylation; overexpression of cyclin D3 partially rescues M33-Meis1-induced growth suppression, linking Meis1 growth-promoting activity to the cyclin D-Rb cell cycle axis.\",\n      \"method\": \"ChIP identifying cyclin D3 as direct target, M33-Meis1 repressor fusion, cell cycle analysis, Rb phosphorylation assay, cyclin D3 rescue experiment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP plus mechanistic rescue experiment defining downstream pathway\",\n      \"pmids\": [\"20237320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Meis1 and Pbx act upstream of gata1 in the erythropoietic transcription factor hierarchy in zebrafish; morpholino knockdown of Meis1 and Pbx causes severe reduction in gata1 expression and failure to produce circulating erythrocytes with increased myeloid cells; gata1 overexpression rescues hemoglobin expression in Pbx/Meis1-depleted embryos.\",\n      \"method\": \"Morpholino knockdown in zebrafish, genetic rescue by gata1 mRNA injection, in situ hybridization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with morpholino knockdown and mRNA rescue; clean pathway placement\",\n      \"pmids\": [\"20123093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ELF1, an ETS transcription factor, directly binds a conserved site 289 bp upstream of the human MEIS1 transcription start site and is required for MEIS1 promoter activity; ELF1 ChIP confirms enrichment at the MEIS1 promoter in MEIS1-expressing cells, and siRNA knockdown of ELF1 reduces MEIS1 expression.\",\n      \"method\": \"Phylogenetic sequence analysis, promoter reporter assay with truncation/mutation, EMSA, ChIP, siRNA knockdown\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP plus mutagenesis plus functional reporter plus knockdown phenotype\",\n      \"pmids\": [\"20600580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MN1-induced leukemogenesis requires the MEIS1/AbdB-like HOX-protein complex; ChIP-seq shows extensive overlap of MN1 and MEIS1 chromatin binding sites; common myeloid progenitors (CMP) but not granulocyte-macrophage progenitors (GMP) can be transformed by MN1, and complementation of GMP with MEIS1/AbdB-like HOX genes restores susceptibility, demonstrating cell-of-origin susceptibility is determined by MEIS1/HOX expression.\",\n      \"method\": \"ChIP-seq, complementation assay in primary bone marrow cells, in vivo leukemia transplantation\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-seq plus genetic complementation with in vivo validation\",\n      \"pmids\": [\"21741595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Meis1 is a critical transcriptional regulator of cardiomyocyte cell cycle arrest; cardiomyocyte-specific Meis1 deletion extends the postnatal proliferative window and reactivates cardiomyocyte mitosis in adult heart without deleterious cardiac function effects; Meis1 overexpression decreases neonatal myocyte proliferation and inhibits neonatal heart regeneration. Meis1 is required for transcriptional activation of CDK inhibitors p15, p16, and p21.\",\n      \"method\": \"Cardiomyocyte-specific conditional knockout, Meis1 overexpression in neonatal heart, cardiomyocyte mitosis assay, cardiac function assessment, target gene expression analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO and OE with multiple phenotypic readouts plus downstream target identification; replicated subsequently\",\n      \"pmids\": [\"23594737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PREP1 and MEIS1 competitively heterodimerize with PBX1 in mouse embryonic fibroblasts; MEIS1 alone transforms Prep1-deficient fibroblasts; PREP1 overexpression inhibits MEIS1 tumorigenicity by sequestering PBX1, which destabilizes MEIS1 protein post-translationally. MEIS1 interaction with DDX3X and DDX5 (identified by Prep1-competition reducing these interactions) is essential for MEIS1-driven tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation, transformation assay in MEFs, protein stability assay, transcriptomic analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, competitive binding, protein stability with functional transformation readout\",\n      \"pmids\": [\"24578510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Conditional Meis1 knockout in adult hematopoietic cells causes significant reduction in hematopoietic stem/progenitor cells due to impaired self-renewal and reduced quiescence in a cell-autonomous manner, resulting in stem cell exhaustion. Meis1 deficiency downregulates Pbx1-dependent HSC signature genes, indicating functional cooperation with Pbx1 in HSC maintenance.\",\n      \"method\": \"Conditional knockout in adult mice (tamoxifen-inducible), FACS enumeration of HSPCs, competitive transplantation, BrdU quiescence assay, gene expression profiling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple functional readouts and mechanistic gene expression data\",\n      \"pmids\": [\"24498346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"C/EBPα is a critical collaborator required for Hoxa9/Meis1-mediated leukemogenesis; over 50% of Hoxa9 genome-wide binding sites are co-bound by C/EBPα; Hoxa9 represses the Cdkn2a/b locus in concert with C/EBPα to overcome G1 cell cycle arrest; C/EBPα loss greatly improves survival in Hoxa9/Meis1-induced leukemia models.\",\n      \"method\": \"ChIP-seq, in vitro transformation assay, murine leukemia model, loss-of-function genetic approach\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide ChIP-seq showing co-occupancy plus genetic loss-of-function with in vivo survival readout\",\n      \"pmids\": [\"24958854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"An RLS-associated intronic SNP (rs12469063) in MEIS1 reduces enhancer activity in the ganglionic eminences of the developing mouse forebrain; CREB1 binds this enhancer and the risk SNP affects CREB1 binding in vitro; heterozygous Meis1-deficient mice exhibit circadian hyperactivity resembling RLS phenotype.\",\n      \"method\": \"Zebrafish and mouse enhancer reporter assays, EMSA for CREB1 binding with allelic variants, heterozygous Meis1 KO behavioral phenotyping\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo enhancer activity assay with allele dependence, in vitro binding assay with mutagenesis, and mouse model phenotype\",\n      \"pmids\": [\"24642863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pbx3 and Meis1 must dimerize to support Hox-induced leukemia; in the absence of Pbx3, Meis1 is rapidly ubiquitinated and degraded via the proteasome. The Meis1 Pbx-binding domain is required to prevent ubiquitination; Pbx3 binding stabilizes Meis1. Additionally, Pbx3 overexpression induces endogenous Meis1 transcription. Meis1/Pbx3 dimerization is required for high-affinity DNA/Hoxa9/Meis1/Pbx3 complex formation in vitro.\",\n      \"method\": \"Deletion analysis, protein half-life assay, proteasome inhibition, in vitro EMSA for quaternary complex, murine leukemia transplantation\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic dissection of protein stability via ubiquitination, in vitro complex reconstitution, in vivo validation\",\n      \"pmids\": [\"25911551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PBX3 and MEIS1 co-expression, without a HOX gene, is sufficient to transform normal mouse hematopoietic stem/progenitor cells and cause AML in vivo, recapitulating the MLL-fusion core transcriptome including endogenous Hoxa gene upregulation; disruption of MEIS1-PBX3 binding abolishes transformation and HOX gene upregulation.\",\n      \"method\": \"Retroviral co-expression in primary mouse HSPC, in vitro transformation assay, in vivo transplantation AML model, gene expression profiling, interaction-disrupting mutants\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vivo leukemia and interaction-disruption mutants\",\n      \"pmids\": [\"26747896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MEIS1 binds an upstream sequence of Pax6 to enhance its transcription in cerebellar granule cell precursors; this Meis1-Pax6 cascade upregulates Smad proteins to enhance BMP signaling, leading to Atoh1 protein degradation in the inner EGL and promoting GCP-to-GC differentiation. Conditional Meis1 KO in the GC lineage causes smaller cerebella with disorganized lobules and ectopic Atoh1-positive GCPs.\",\n      \"method\": \"Conditional cerebellar KO, ChIP for Pax6 upstream sequence, in vitro promoter assay, Smad/BMP pathway analysis, Atoh1 expression analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP identifying direct target plus conditional KO with pathway dissection\",\n      \"pmids\": [\"29317485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sequential and mutually exclusive binding of MEIS1 and NKX2-5 to overlapping sites on the Popdc2 cardiac gene enhancer provides a mechanism for spatiotemporal regulation: as cardiac progenitors differentiate, they sequentially experience high MEIS1 then increasing NKX2-5, whose binding displaces MEIS1 from shared target sites to switch transcriptional output.\",\n      \"method\": \"ChIP, reporter assays, in vitro binding competition assay, expression profiling during cardiac differentiation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP plus in vitro competition assay establishing mutually exclusive binding mechanism\",\n      \"pmids\": [\"26411676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Meis1 regulates a HLF-oxidative stress axis in MLL leukemia: Meis1 loss leads to increased oxidative stress, oxygen flux, and apoptosis in leukemic cells; ChIP and gene expression studies identify HLF as a direct Meis1 target gene; hypoxia or HLF expression rescues leukemia development in Meis1-deficient cells.\",\n      \"method\": \"Inducible Meis1-knockout crossed with MLL-AF9 knockin mice, ChIP for HLF promoter, oxidative stress measurement, HLF rescue experiment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP identifying direct target plus genetic rescue demonstrating mechanistic pathway\",\n      \"pmids\": [\"25740828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MEIS1 promoter is hypomethylated and transcriptionally reactivated in DNMT3A-mutant AML patients; whole-genome bisulfite sequencing and DNA methylation microarrays identify MEIS1 as the key gene undergoing promoter hypomethylation-associated reactivation, providing an alternative (MLL-fusion-independent) mechanism for engaging MEIS1-dependent oncogenic transcription.\",\n      \"method\": \"Whole-genome bisulfite sequencing, DNA methylation microarrays in patient samples\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide bisulfite sequencing with patient samples; single study linking DNMT3A mutation to MEIS1 epigenetic reactivation\",\n      \"pmids\": [\"26434589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MEIS1 promotes leukemic cell homing and engraftment in bone marrow through transactivation of synaptotagmin-like 1 (SYTL1/SLP1); ChIP in leukemic cells shows MEIS1 directly binds the SYTL1 gene; SYTL1 replacement in MEIS1-deficient cells restores cell migration and engraftment; SYTL1 activates CXCL12/CXCR4 signaling by regulating intracellular trafficking of CXCR4.\",\n      \"method\": \"ChIP for SYTL1 promoter, MEIS1 deficiency murine model, SYTL1 rescue experiment, CXCR4 trafficking assay, migration assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP identifying direct target plus genetic rescue plus receptor trafficking mechanistic readout\",\n      \"pmids\": [\"27018596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hoxa9 and Meis1 cooperatively suppress miR-146a to upregulate Syk expression and activity in AML; Meis1 regulates Syk indirectly through PU.1-dependent regulation of miR-146a, which directly targets Syk; Syk signaling in turn induces Meis1 in the context of Hoxa9, creating a regulatory feedback loop; Syk inhibition disrupts this loop and prolongs survival of Hoxa9/Meis1 AML mice.\",\n      \"method\": \"(Phospho)proteomic analysis, miR-146a target validation for Syk, ChIP/reporter assays for PU.1-miR-146a axis, Syk inhibitor treatment in murine AML model\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — proteomics plus miRNA target validation plus in vivo pharmacologic target validation\",\n      \"pmids\": [\"28399410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PPM1K (a mitochondrial Ser/Thr phosphatase promoting BCAA catabolism) maintains MEIS1 and p21 protein levels by decreasing CDC20-mediated ubiquitination and degradation; PPM1K deficiency reduces MEIS1/p21 signaling, impairs HSC glycolysis and quiescence, and decreases repopulation; PPM1K deletion also extends survival in a murine leukemia model.\",\n      \"method\": \"Genetically encoded BCAA fluorescent sensor, conditional KO, ubiquitination assay, HSC functional assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination mechanistic assay plus conditional KO with multiple functional readouts\",\n      \"pmids\": [\"29719258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MEIS1 controls human hematopoiesis from pluripotent stem cells in a stage-specific manner: it is required for specification of APLNR+ mesoderm progenitors to functional hemogenic endothelial progenitors (via TAL1 as downstream mediator), and is separately required for megakaryopoiesis/thrombopoiesis (via FLI1 as downstream target); mechanistic ChIP or promoter binding for TAL1 and FLI1 within this context was demonstrated.\",\n      \"method\": \"hPSC differentiation, MEIS1 overexpression/knockdown, ChIP for TAL1 and FLI1, functional hematopoietic assays\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP identifying direct targets plus stage-specific functional dissection in human stem cell model\",\n      \"pmids\": [\"29358086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MEIS1 directly binds two specific sites in the SKOR1 promoter to positively regulate SKOR1 expression; an RLS-associated SNP in the SKOR1 promoter region modifies MEIS1-driven activation, directly linking two GWAS-identified RLS genes through a transcriptional regulatory relationship.\",\n      \"method\": \"MEIS1 ChIP at SKOR1 promoter sites, promoter reporter assay with site mutagenesis, allele-specific reporter assay with RLS SNP\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP plus mutagenesis of binding sites plus allele-specific functional assay\",\n      \"pmids\": [\"30111810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MEIS1 interacts directly with the androgen receptor (AR) protein; co-immunoprecipitation and GST pull-down confirm a protein-protein interaction; MEIS1 modulates AR cytoplasm/nucleus translocation, reduces AR recruitment to the PSA gene promoter androgen response element, and promotes recruitment of corepressors NCoR and SMRT in the presence of androgen, acting as a novel AR co-repressor.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, nuclear fractionation, ChIP for AR at PSA promoter, reporter assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal pulldown plus ChIP plus functional localization assay\",\n      \"pmids\": [\"25158280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MEIS1 suppression in fetal cardiomyocytes (siRNA) increases maximal oxygen consumption and mitochondrial activity while decreasing expression of glycolytic genes, demonstrating that MEIS1 actively suppresses oxidative phosphorylation and promotes glycolysis in the developing cardiomyocyte; the normal developmental downregulation of MEIS1 around birth underlies the perinatal metabolic switch.\",\n      \"method\": \"siRNA knockdown in primary fetal sheep cardiomyocytes, Seahorse metabolic flux analysis, MitoTracker staining, gene expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with direct metabolic readout (Seahorse) in primary cells\",\n      \"pmids\": [\"30884246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Meis1 inactivation in mouse neural crest leads to altered sympatho-vagal cardiac regulation and increased susceptibility to sudden cardiac death; Meis1-deficient sympathetic neurons die by apoptosis from embryonic to perinatal stages; Meis1 regulates transcription of key molecules for the endosomal machinery, and Rab5+ endosome trafficking is severely altered in Meis1-inactivated sympathetic neurons.\",\n      \"method\": \"Neural crest-specific conditional Meis1 knockout, cardiac electrophysiology, sympathetic neuron survival assay, endosome trafficking analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific conditional KO with multiple mechanistic cellular readouts\",\n      \"pmids\": [\"26857994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Gfi1b directly represses Meis1 transcription in the erythroid lineage but not in megakaryocytes; Gfi1b and its cofactors LSD1 and CoREST occupy distinct regions of the Meis1 promoter in erythroid cells; LSD1 inhibition upregulates Meis1 specifically in erythroid cells; the repression requires the Gfi1b SNAG domain and DNA binding domain as shown by transfection of mutant forms.\",\n      \"method\": \"ChIP for Gfi1b/LSD1/CoREST at Meis1 promoter, LSD1 inhibitor treatment, gfi1b knockout fetal liver, promoter reporter assay with Gfi1b mutants\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP plus mutagenesis of repressor domain plus KO and inhibitor phenotype\",\n      \"pmids\": [\"23308270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MEIS1 transcription is epigenetically suppressed in colorectal cancer by EZH2-DNMT3a recruited by lncRNA ELFN1-AS1 to the MEIS1 promoter; MEIS1 suppression drives oxaliplatin resistance through enhanced FEN1 expression; EZH2 inhibitor GSK126 or ELFN1-AS1 ASO restores MEIS1 expression and reverses resistance.\",\n      \"method\": \"lncRNA-protein complex analysis, ChIP for EZH2/DNMT3a at MEIS1 promoter, FEN1 expression assay, in vivo tumor xenograft, drug resistance assay\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP demonstrating epigenetic complex at MEIS1 promoter plus in vitro and in vivo functional validation\",\n      \"pmids\": [\"35351858\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MEIS1 is a TALE-class homeodomain transcription factor that functions primarily as a nuclear transcriptional regulator by forming cooperative DNA-binding complexes with PBX family proteins and AbdB-like HOX proteins (notably HOXA9), regulating target genes including p15/p16/p21 (cell cycle arrest in cardiomyocytes), FLT3/CD34 (HSC and leukemia stem cell identity), cyclin D3 and HLF (cell cycle and metabolic control), SYTL1 (bone marrow homing via CXCR4 trafficking), TAL1/FLI1 (hemogenic endothelium and megakaryopoiesis), and SKOR1 (neural development linked to RLS); PBX binding stabilizes MEIS1 protein against CDC20/ubiquitin-proteasome-mediated degradation; GSK-3 promotes CREB/CBP/TORC co-activator assembly on MEIS1 to drive HOX-dependent transcription; ELF1 directly activates MEIS1 transcription, while Gfi1b/LSD1/CoREST repress it in erythroid cells and EZH2/DNMT3a repress it epigenetically in cancer; MEIS1 is rate-limiting for MLL-fusion leukemia stem cell self-renewal and is required for definitive hematopoiesis, megakaryocyte production, angiogenesis, sympathetic neuron survival, cardiomyocyte cell cycle arrest, cerebellar granule cell differentiation, and proximodistal limb patterning.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MEIS1 is a TALE-class homeodomain transcription factor that orchestrates cell fate decisions across hematopoiesis, cardiac development, limb patterning, and neural differentiation by forming cooperative DNA-binding complexes with PBX and HOX family proteins. MEIS1 heterodimerizes with PBX proteins through a conserved N-terminal domain distinct from the HOX-interaction interface, and assembles trimeric MEIS1–PBX–HOXA9 complexes on composite DNA elements to activate target genes including FLT3, cyclin D3, HLF, SYTL1, TAL1, FLI1, PAX6, and SKOR1; GSK-3 promotes recruitment of CREB/CBP/TORC coactivators to MEIS1, and PBX binding stabilizes MEIS1 protein by preventing CDC20-mediated ubiquitin–proteasome degradation [PMID:9343407, PMID:10082572, PMID:20541704, PMID:29719258]. MEIS1 is essential for definitive hematopoiesis, megakaryopoiesis, and HSC quiescence; its deletion causes embryonic lethality with hemorrhage and vascular defects, while in adult HSCs it maintains self-renewal and glycolytic metabolism [PMID:14713950, PMID:24498346, PMID:30884246]. MEIS1 is a rate-limiting driver of MLL-fusion leukemia stem cell self-renewal and independently controls cardiomyocyte cell-cycle arrest through activation of p15/p16/p21, sympathetic neuron survival via endosomal trafficking, cerebellar granule cell differentiation via PAX6–BMP signaling, and proximodistal limb patterning [PMID:17942707, PMID:23594737, PMID:26857994, PMID:29317485, PMID:10586884].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of MEIS1 as a TALE-class homeobox gene at a retroviral insertion site in myeloid leukemia established it as a candidate oncogene and founding member of a new homeodomain subfamily.\",\n      \"evidence\": \"cDNA cloning, Northern blot, and retroviral insertional mutagenesis in BXH-2 mice\",\n      \"pmids\": [\"7565694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No DNA-binding specificity or partner proteins yet identified\", \"Mechanism of leukemogenic activation unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstration that MEIS1 forms cooperative DNA-binding heterodimers with both AbdB-like HOX proteins and PBX1 via distinct interaction interfaces defined the two-partner binding logic that underlies all subsequent MEIS1 function.\",\n      \"evidence\": \"EMSA with purified proteins, cooperative binding kinetics, deletion mapping distinguishing PBX- vs HOX-interaction domains\",\n      \"pmids\": [\"9343407\", \"9405651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No trimeric complex yet demonstrated\", \"In vivo relevance of these interactions not established\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Reconstitution of a trimeric HOXA9–PBX2–MEIS1 complex in myeloid nuclei and demonstration that MEIS1/Hth drives PBX/EXD nuclear import established the core transcriptional unit and explained how MEIS1 controls partner activity in vivo.\",\n      \"evidence\": \"Co-IP from myeloid nuclear extracts, EMSA for trimeric complex, Drosophila hth genetic epistasis, chick limb ectopic expression\",\n      \"pmids\": [\"10082572\", \"9463350\", \"10586884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide target genes unknown\", \"Relative contribution of PBX nuclear import vs direct transcriptional activation not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing that PREP1 cannot substitute for MEIS1 in HOXA9-induced AML despite shared PBX-binding ability revealed that MEIS1 leukemogenic function extends beyond PBX nuclear retention to include unique transactivation or target-gene selection.\",\n      \"evidence\": \"Retroviral co-expression and bone marrow transplantation leukemia model\",\n      \"pmids\": [\"11113197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Unique MEIS1 domains responsible for leukemogenic specificity not mapped\", \"Direct transcriptional targets in leukemia unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Germline Meis1 knockout and identification of Meis1 as a critical downstream effector of MLL-ENL together established MEIS1 as essential for definitive hematopoiesis, megakaryopoiesis, angiogenesis, and HSC function, and as a key mediator of MLL-fusion leukemogenesis.\",\n      \"evidence\": \"Meis1-/- mouse embryonic lethality with hemorrhage and HSC failure; inducible MLL-ENL system showing Hoxa9+Meis1 substitutes for MLL-ENL\",\n      \"pmids\": [\"14713950\", \"14701735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomous vs non-cell-autonomous contributions not fully separated\", \"Direct MEIS1 target genes in HSCs not yet identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Structure–function analysis showed that MEIS1 programs leukemia stem cell identity through PBX-dependent induction of HSC genes (FLT3, CD34), requiring PBX binding, DNA binding, and a C-terminal transactivation domain.\",\n      \"evidence\": \"Domain deletion mutants in retroviral transformation and leukemia transplantation assays\",\n      \"pmids\": [\"15755900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FLT3 alone is sufficient for MEIS1 leukemogenic effect unclear\", \"Structural basis of C-terminal domain function unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"ChIP demonstration that MEIS1 and HOXA9 co-occupy the FLT3 promoter, combined with VP16-Meis1 acting as an autonomous oncogene that activates endogenous HOX genes, proved direct promoter co-occupancy and revealed bidirectional HOX-MEIS1 regulatory feedback.\",\n      \"evidence\": \"VP16/engrailed fusion proteins, ChIP on Flt3 promoter, retroviral transformation assays\",\n      \"pmids\": [\"16648484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide co-occupancy maps not yet available\", \"Mechanism of endogenous HOX activation by VP16-Meis1 not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Multiple loss-of-function approaches established MEIS1 as the rate-limiting factor for MLL leukemia stem cell self-renewal, quantitatively controlling LSC frequency, and identified Pbx2/Pbx3 redundancy as the PBX partner requirement.\",\n      \"evidence\": \"Conditional knockout, shRNA, dominant-negative in MLL-transformed cells with in vivo LSC frequency assay\",\n      \"pmids\": [\"17942707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific MEIS1 target genes mediating self-renewal vs differentiation arrest not separated\", \"Whether MEIS1 is druggable in this context unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that GSK-3 promotes CREB/TORC/CBP coactivator assembly on MEIS1 provided the first cofactor-recruitment mechanism for MEIS1 transcriptional activation in HOX-dependent leukemia, while identification of cyclin D3 as a direct target linked MEIS1 to the cell cycle machinery.\",\n      \"evidence\": \"Co-IP of CREB/TORC/CBP with MEIS1, GSK-3 inhibition, ChIP identifying cyclin D3, M33-Meis1 repressor with rescue\",\n      \"pmids\": [\"20541704\", \"20237320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GSK-3 kinase activity mechanistically promotes coactivator assembly on MEIS1 not resolved at molecular level\", \"Whether cyclin D3 is required for leukemia in vivo not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"ChIP-seq revealed extensive genome-wide co-occupancy of MN1 and MEIS1 and showed that cell-of-origin susceptibility to MN1 leukemia is determined by MEIS1/HOX expression levels, establishing MEIS1 as a gatekeeper of oncogenic competence.\",\n      \"evidence\": \"ChIP-seq, genetic complementation of GMP with MEIS1/AbdB-HOX, in vivo transplantation\",\n      \"pmids\": [\"21741595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MN1 and MEIS1 physically interact or just co-bind DNA not determined\", \"Full set of co-regulated target genes not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Cardiomyocyte-specific Meis1 deletion extended postnatal proliferation and reactivated adult cardiomyocyte mitosis, while Gfi1b/LSD1/CoREST were shown to repress Meis1 in erythroid cells, revealing MEIS1 as a master regulator of cell-cycle exit and demonstrating lineage-specific epigenetic control of MEIS1 itself.\",\n      \"evidence\": \"Cardiomyocyte-specific conditional KO and OE with mitosis and cardiac function readouts; ChIP for Gfi1b/LSD1/CoREST at Meis1 promoter in erythroid cells\",\n      \"pmids\": [\"23594737\", \"23308270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MEIS1 deletion enables functional cardiac regeneration after injury not shown\", \"Gfi1b repression mechanism limited to erythroid lineage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Conditional adult Meis1 KO showed HSC exhaustion due to impaired quiescence and self-renewal, PREP1 was found to antagonize MEIS1 by competing for PBX binding and destabilizing MEIS1 protein, and an RLS-associated SNP was shown to reduce MEIS1 enhancer activity via impaired CREB1 binding, broadening MEIS1 biology to stem cell homeostasis and neurological disease.\",\n      \"evidence\": \"Adult conditional KO with FACS/transplantation; PREP1 competition assays with protein stability readout; enhancer reporter assays with allelic variants and Meis1+/- behavioral phenotyping\",\n      \"pmids\": [\"24498346\", \"24578510\", \"24642863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which MEIS1 haploinsufficiency produces RLS-like behavior not molecularly defined\", \"Identity of DDX3X/DDX5 functional role in MEIS1 tumorigenesis not elaborated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"PBX3 binding was shown to stabilize MEIS1 by preventing ubiquitin-proteasome degradation, PBX3–MEIS1 co-expression alone was sufficient for AML, and MEIS1 was found to regulate a HLF-oxidative-stress axis and SYTL1-CXCR4 trafficking in leukemia, defining protein stability control and multiple downstream effector pathways.\",\n      \"evidence\": \"Ubiquitination assays with proteasome inhibition; PBX3+MEIS1 co-expression leukemia model; ChIP for HLF and SYTL1; oxidative stress and migration rescue experiments\",\n      \"pmids\": [\"25911551\", \"26747896\", \"25740828\", \"27018596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible for MEIS1 ubiquitination not identified (CDC20 link came later)\", \"Whether HLF and SYTL1 pathways are independent or convergent unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Neural crest-specific Meis1 knockout revealed a requirement for sympathetic neuron survival and endosomal trafficking regulation, linking MEIS1 to Rab5+ endosome function and cardiac autonomic control including susceptibility to sudden cardiac death.\",\n      \"evidence\": \"Neural crest-specific conditional KO, sympathetic neuron apoptosis assay, Rab5 endosome trafficking analysis, cardiac electrophysiology\",\n      \"pmids\": [\"26857994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets mediating endosomal machinery regulation not fully identified\", \"Whether this mechanism operates in other neuronal populations unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Multiple studies defined new MEIS1 transcriptional targets and regulatory axes: PPM1K was shown to maintain MEIS1 protein by opposing CDC20-mediated ubiquitination in HSCs; MEIS1 was found to drive hemogenic endothelium specification via TAL1 and megakaryopoiesis via FLI1; MEIS1 directly activates SKOR1 at an RLS SNP-modifiable promoter; and MEIS1 acts as an AR corepressor recruiting NCoR/SMRT.\",\n      \"evidence\": \"CDC20 ubiquitination assays, PPM1K conditional KO; hPSC differentiation with ChIP for TAL1/FLI1; SKOR1 promoter ChIP and allele-specific reporter; AR co-IP, GST pulldown, ChIP at PSA promoter\",\n      \"pmids\": [\"29719258\", \"29358086\", \"30111810\", \"25158280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PPM1K–CDC20–MEIS1 axis not confirmed in leukemia context\", \"AR corepressor function studied in prostate cancer cells only\", \"SKOR1 regulation link to RLS pathophysiology not mechanistically complete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Metabolic flux analysis in cardiomyocytes demonstrated that MEIS1 actively suppresses oxidative phosphorylation and promotes glycolysis, establishing the mechanistic basis for the perinatal metabolic switch accompanying cardiomyocyte cell-cycle arrest.\",\n      \"evidence\": \"siRNA knockdown in primary fetal cardiomyocytes with Seahorse metabolic flux analysis\",\n      \"pmids\": [\"30884246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets mediating metabolic reprogramming not identified\", \"Whether metabolic shift is separable from cell-cycle arrest not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Epigenetic silencing of MEIS1 by EZH2–DNMT3a recruited by lncRNA ELFN1-AS1 was shown to drive oxaliplatin resistance in colorectal cancer through FEN1 upregulation, revealing an MLL-independent mechanism of MEIS1 suppression with therapeutic implications.\",\n      \"evidence\": \"ChIP for EZH2/DNMT3a at MEIS1 promoter, lncRNA–protein interaction assays, FEN1 expression, xenograft drug resistance model\",\n      \"pmids\": [\"35351858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MEIS1 directly represses FEN1 or acts indirectly not resolved\", \"Generalizability to other cancer types not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structural model of the MEIS1–PBX–HOX trimeric complex on DNA, the full catalog of direct MEIS1 genomic targets across normal tissues, and the mechanism by which MEIS1 haploinsufficiency causes restless legs syndrome-related neuronal phenotypes remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of MEIS1-containing trimeric complex\", \"Genome-wide MEIS1 target maps in non-leukemic tissues largely absent\", \"Neuronal cell types and circuits through which MEIS1 contributes to RLS not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 2, 3, 6, 9, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [12, 13, 19, 23, 30, 32, 34, 37, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 12, 13, 19, 21, 23, 30, 32, 37, 38, 42]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 10, 16, 30, 41]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [19, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 25, 37]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 11, 14, 22, 29, 33, 43]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [42, 43]}\n    ],\n    \"complexes\": [\n      \"MEIS1-PBX heterodimer\",\n      \"MEIS1-PBX-HOXA9 trimer\",\n      \"MEIS1-CREB-CBP-TORC coactivator complex\"\n    ],\n    \"partners\": [\n      \"PBX1\",\n      \"PBX2\",\n      \"PBX3\",\n      \"HOXA9\",\n      \"CREB1\",\n      \"CBP\",\n      \"DDX3X\",\n      \"AR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}