{"gene":"HOXA9","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1998,"finding":"HOXA9 transforms primary bone marrow cells through selective collaboration with MEIS1a but not PBX1b; co-expression of HOXA9 and MEIS1a induces growth factor-dependent acute myeloid leukemia in mice, while HOXA9+PBX1b fails to transform cells acutely.","method":"Retroviral overexpression in primary bone marrow cells, mouse transplantation model, FDC-P1 cell transplantation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined cellular transformation phenotype with genetic epistasis (MEIS1a vs PBX1b), replicated in two cell systems (primary bone marrow and FDC-P1)","pmids":["9649441"],"is_preprint":false},{"year":1996,"finding":"The t(7;11)(p15;p15) chromosomal translocation creates an in-frame genomic fusion between HOXA9 and NUP98, generating a chimeric NUP98/HOXA9 transcript containing the NUP98 amino-terminal half fused to the HOXA9 homeodomain.","method":"Chromosomal translocation mapping, molecular cloning, transcript analysis in three AML patients","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct molecular identification of fusion gene in three independent patients, foundational structural finding replicated across labs","pmids":["8563753"],"is_preprint":false},{"year":1999,"finding":"NUP98-HOXA9 fusion protein acts as an aberrant transcription factor: the NUP98 FG repeats function as potent transactivation domains by physically interacting with coactivators CBP and p300, while the HOXA9 homeodomain provides DNA-binding and PBX heterodimerization; both activities are required for NIH 3T3 transformation.","method":"NIH 3T3 transformation assay, transactivation reporter assays, co-immunoprecipitation of CBP/p300 with FG repeats, domain mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro transformation, direct binding (Co-IP), mutagenesis of FG repeats and HOXA9 domains, multiple orthogonal methods in one study","pmids":["9858599"],"is_preprint":false},{"year":1999,"finding":"HOXA9 forms trimeric complexes with PBX2 and MEIS1 in myeloid cells: MEIS1 enhances HOXA9-PBX complex formation in the absence of DNA, and the three proteins co-immunoprecipitate from myeloid cell nuclear extracts; co-localization occurs in nuclear speckles.","method":"EMSA, DNA site selection, co-immunoprecipitation from myeloid cell nuclear extracts, immunofluorescence co-localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP from nuclear extracts, EMSA trimeric complex, immunofluorescence co-localization, multiple orthogonal methods","pmids":["10082572"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of HoxA9 complexed with Pbx1 and DNA at 1.9 Å resolution reveals that the posterior Hox hexapeptide adopts an altered conformation compared to anterior HOX/PBC structures, providing stronger DNA-binding affinity and altered specificity; residues in the N-terminal arm of the homeodomain are critical for DNA sequence recognition through indirect contacts.","method":"X-ray crystallography (1.9 Å), DNA-binding mutagenesis of HoxA9 and HoxB1","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional mutagenesis validation, mechanistically definitive","pmids":["12923056"],"is_preprint":false},{"year":2003,"finding":"CUL-4A ubiquitylation machinery controls HOXA9 protein stability by promoting its ubiquitylation and proteasome-dependent degradation; the HOXA9 homeodomain is required for CUL-4A-mediated degradation; interference with CUL-4A biosynthesis alters HOXA9 steady-state levels and impairs granulocyte differentiation of 32D myeloid progenitors.","method":"Ubiquitylation assay, proteasome inhibition, RNAi knockdown of CUL-4A, ectopic CUL-4A expression, 32D cell differentiation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical ubiquitylation assay, domain mapping (homeodomain required), RNAi + overexpression with defined cellular phenotype","pmids":["14609952"],"is_preprint":false},{"year":2004,"finding":"HOXA9 is phosphorylated by protein kinase C (PKC) on Ser204 and Thr205 within the N-terminal region of the homeodomain; PKC-mediated phosphorylation decreases HOXA9 DNA-binding affinity in vitro and reduces cooperative DNA-binding with PBX; PKC inhibition reduces phorbol ester-induced myeloid differentiation, linking HOXA9 phosphorylation to differentiation regulation.","method":"In vitro kinase assay with purified HOXA9, site-directed mutagenesis, EMSA, phorbol ester/PKC inhibitor treatment of PLB985 and HOXA9-immortalized murine marrow cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro phosphorylation with site mutagenesis, EMSA functional consequence, cellular phenotype with pharmacologic validation","pmids":["15082777"],"is_preprint":false},{"year":2001,"finding":"HOXA9 binds to a Hox binding site in the osteopontin (OPN) promoter and acts as a transcriptional repressor of OPN; Smad4 physically interacts with HOXA9 (co-immunoprecipitation from cotransfected COS-1 cells) and displaces HOXA9 from its cognate DNA site in response to TGF-β stimulation, thereby derepressing OPN transcription.","method":"Gel shift (EMSA) with GST-Smad3, co-immunoprecipitation of FLAG-Smad4 with HA-HOXA9, luciferase reporter transfection assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP of interaction, EMSA displacement assay, reporter assay; multiple orthogonal methods in single study","pmids":["11042172"],"is_preprint":false},{"year":2005,"finding":"HOXA9 activates transcription of the CYBB gene (encoding gp91Phox) in differentiated myeloid cells via a cis-element in the proximal promoter; this activation requires PBX1 and is inhibited by MEIS1; phosphorylation of conserved homeodomain tyrosines increases HOXA9 binding to the CYBB promoter; the NUP98-HOXA9 fusion has greater binding affinity but is unresponsive to tyrosine phosphorylation and blocks CYBB transcription.","method":"Reporter gene assays, EMSA, promoter binding studies, phosphorylation assays, expression in myeloid cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays and EMSA in single lab, multiple functional readouts","pmids":["15681849"],"is_preprint":false},{"year":2005,"finding":"HDAC activity is required for HoxA9 expression in adult progenitor cells; HoxA9 acts as a master switch to regulate endothelial-committed genes (eNOS, VEGFR2, VE-cadherin) and mediates shear stress-induced endothelial maturation; HoxA9-deficient mice show reduced endothelial progenitor cells and impaired postnatal neovascularization.","method":"HDAC inhibitor treatment, HoxA9 overexpression rescue experiments, siRNA knockdown, HoxA9 knockout mouse model with ischemia assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — rescue experiment, KO mouse with specific vascular phenotype, knockdown/overexpression with defined target gene readouts","pmids":["15928198"],"is_preprint":false},{"year":2007,"finding":"Pim1 kinase is a direct transcriptional target of HOXA9; HOXA9 protein binds the Pim1 promoter and induces Pim1 mRNA and protein in hematopoietic cells; Pim1 induction by HOXA9 increases phosphorylation and inactivation of pro-apoptotic BAD; Hoxa9-/- cells show increased apoptosis and decreased proliferation that are rescued by Pim1 reintroduction.","method":"Chromatin immunoprecipitation (ChIP), quantitative RT-PCR, Western blot, Hoxa9-/- mouse cells, Pim1 rescue experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct promoter binding, KO rescue experiment, BAD phosphorylation mechanistic readout","pmids":["17327400"],"is_preprint":false},{"year":2007,"finding":"HOXA9 inhibits NF-κB-dependent activation of endothelial cells; HOXA9 overexpression inhibits induction of ICAM-1, VCAM-1, and E-selectin in response to pro-inflammatory cytokines by interfering with NF-κB DNA binding (but not its transactivation capacity or nuclear localization).","method":"Luciferase reporter assays with NF-κB-dependent promoters, EMSA for NF-κB DNA binding, HOXA9 overexpression in endothelial cells","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and reporter assays in single lab, mechanistic pathway placement","pmids":["17586512"],"is_preprint":false},{"year":2007,"finding":"NF-κB activation is required for HOXA9 transcriptional downregulation during endothelial cell activation; HOXA9 positively autoregulates its own expression requiring both its DNA-binding and transactivation domains.","method":"HOXA9 promoter deletion analysis, reporter assays in endothelial cells and NF-κB knockout cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter deletion mapping with reporter assays, NF-κB KO cells as genetic validation, single lab","pmids":["18068911"],"is_preprint":false},{"year":2008,"finding":"MLL binds to specific CpG clusters within the Hoxa9 locus and protects them from DNA methylation, thereby maintaining Hoxa9 transcript expression; shRNA knockdown of MLL reverses methylation protection at these CpG clusters; reconstituting MLL expression in Mll-null cells reverses DNA methylation, demonstrating a dominant protective effect.","method":"ChIP of MLL at Hoxa9 locus, bisulfite sequencing of CpG methylation, shRNA knockdown of Mll, Mll-null cell reconstitution","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, bisulfite sequencing, shRNA knockdown, and reconstitution in Mll-null cells with multiple orthogonal methods","pmids":["18483194"],"is_preprint":false},{"year":2008,"finding":"miR-126 targets highly conserved sites within the HOXA9 homeobox coding sequence; forced expression of miR-126 downregulates HOXA9 protein and causes loss of biological activity in HOXA9-immortalized bone marrow cells; inhibition of endogenous miR-126 increases HOXA9 protein.","method":"Forced miRNA expression, luciferase reporter targeting assays, Western blot for HOXA9 protein, miR-126 inhibitor in F9 cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated targeting of homeobox sequence, gain- and loss-of-function, single lab","pmids":["18474618"],"is_preprint":false},{"year":2008,"finding":"HOXA9 suppression in MLL-rearranged leukemia cells induces proliferation arrest and apoptosis and co-downregulates HOXA10, MEIS1, PBX3, and MEF2C; HOXA9 depletion reduces leukemia burden in vivo in mice transplanted with t(4;11) SEMK2 cells.","method":"RNA interference knockdown, gene expression profiling, apoptosis assays, in vivo mouse leukemia model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi with expression profiling, in vivo xenograft validation, defined apoptosis phenotype","pmids":["19056693"],"is_preprint":false},{"year":2010,"finding":"HOXA9 directly modulates BRCA1 expression to restrict breast tumor behavior; restoring HOXA9 expression represses growth and survival of breast cancer cells in culture and xenograft models; wild-type BRCA1 phenocopies HOXA9 tumor suppressor function, and reducing BRCA1 inhibits HOXA9 anti-tumor activity.","method":"HOXA9 overexpression and knockdown, xenograft mouse model, molecular correlation studies, BRCA1 ectopic expression rescue","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft with rescue experiments, epistasis between HOXA9 and BRCA1, single lab","pmids":["20389018"],"is_preprint":false},{"year":2012,"finding":"PRMT5 is a TNF-α-dependent binding partner of HOXA9 (identified by mass spectrometry); PRMT5 induces symmetric dimethylation of Arg140 on HOXA9, which is essential for HOXA9-dependent E-selectin induction; PRMT5 is recruited to the E-selectin promoter following HOXA9 binding; siRNA depletion of PRMT5 abrogates stimulus-dependent HOXA9 methylation and E-selectin/VCAM-1 induction.","method":"Mass spectrometry protein identification, Co-IP, siRNA depletion, ChIP, site-directed mutagenesis of Arg140","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — MS-identified interaction, site-specific mutagenesis of methylation site, ChIP, siRNA with defined molecular phenotype","pmids":["22269951"],"is_preprint":false},{"year":2012,"finding":"PBX3, but not PBX1 or PBX2, is a critical cofactor of HOXA9 in leukemogenesis; PBX3 depletion significantly inhibits MLL-fusion-mediated cell transformation; co-expressed PBX3 synergizes with HOXA9 in promoting cell transformation in vitro and leukemogenesis in vivo; a peptide (HXR9) disrupting HOX-PBX interactions selectively kills leukemic cells overexpressing HOXA/PBX3.","method":"shRNA depletion of PBX3, retroviral co-expression of HOXA9+PBX3, in vivo leukemogenesis mouse model, HXR9 peptide treatment assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function shRNA, gain-of-function co-expression, in vivo leukemogenesis with defined synergistic phenotype","pmids":["23264595"],"is_preprint":false},{"year":2012,"finding":"HOXA9 expression in ovarian cancer cells induces normal peritoneal fibroblasts to acquire cancer-associated fibroblast (CAF) markers; these effects are due substantially to HOXA9 transcriptional activation of TGF-β2, which acts in a paracrine manner to induce CXCL12, IL-6, and VEGF-A in fibroblasts/MSCs.","method":"HOXA9 overexpression in EOC cells, fibroblast co-culture, xenograft mouse model, TGF-β2 promoter analysis","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft with defined paracrine mechanism via TGF-β2, single lab","pmids":["22945634"],"is_preprint":false},{"year":2013,"finding":"HMGA2 depletion induces TET1 expression; TET1 binds and demethylates its own promoter and the HOXA gene promoters (including HOXA9) to enhance HOXA gene expression; both TET1 and HOXA9 suppress breast tumor growth and metastasis in mouse xenografts.","method":"ChIP, bisulfite sequencing/methylation analysis, xenograft mouse models, HMGA2 depletion","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for TET1 binding, methylation assay, xenograft with defined signaling pathway, single lab","pmids":["23716660"],"is_preprint":false},{"year":2013,"finding":"JMJD1C directly interacts with HOXA9 and modulates a HOXA9-controlled gene-expression program; loss of JMJD1C substantially decreases leukemia stem cell (LSC) frequency and causes differentiation of MLL-AF9- and HOXA9-driven leukemias, while having only minor effects on normal hematopoietic stem cell self-renewal.","method":"Co-immunoprecipitation (JMJD1C-HOXA9 interaction), conditional knockout mouse model, in vivo shRNA screen, LSC frequency assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction (Co-IP), conditional KO with defined LSC phenotype, in vivo shRNA screen","pmids":["26878175"],"is_preprint":false},{"year":2013,"finding":"HoxA9 maintains Bcl-2 expression in hematopoietic cells; maintenance of HoxA9 overexpression is required for continued cell survival even in the presence of growth factors; hematopoietic cells lacking Bcl-2 are not immortalized by HoxA9 in vitro; deletion of Bcl-2 delays onset and reduces severity of HoxA9/Meis1 and MLL-AF9 leukemias.","method":"Inducible HoxA9 system (4-OHT-regulated), Bcl-2 knockout cells, in vivo leukemia mouse model with Bcl-2 deletion","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (Bcl-2 KO in HoxA9 context), in vivo leukemia model with survival readout","pmids":["24177192"],"is_preprint":false},{"year":2013,"finding":"SALL4 binds the HOXA9 promoter, and SALL4 overexpression leads to enhanced binding of histone activation markers at the HOXA9 promoter and increased HOXA9 expression; SALL4 co-occupies the HOXA9 promoter with MLL in AML cells (co-immunoprecipitation between SALL4 and MLL), suggesting a SALL4/MLL pathway controlling HOXA9 expression.","method":"ChIP of SALL4 at HOXA9 promoter, co-immunoprecipitation of SALL4 and MLL, histone modification ChIP, shRNA knockdown in leukemic cells","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP, single lab, mechanistic pathway placement","pmids":["24051379"],"is_preprint":false},{"year":2014,"finding":"C/EBPα is a critical collaborator required for Hoxa9/Meis1-mediated leukemogenesis; C/EBPα loss greatly improves survival in primary and secondary murine Hoxa9/Meis1 leukemia models; >50% of Hoxa9 genome-wide binding sites are co-occupied by C/EBPα; Hoxa9 and C/EBPα co-repress the Cdkn2a/b locus to overcome G1 cell cycle block.","method":"ChIP-seq (genome-wide co-occupancy), loss-of-function mouse models, cell proliferation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq genome-wide co-occupancy, primary and secondary in vivo leukemia models with defined phenotype","pmids":["24958854"],"is_preprint":false},{"year":2006,"finding":"Cdx4 and menin bind the same regulatory region of the Hoxa9 locus in vivo and co-activate Hoxa9 reporter gene expression; ablation of menin abrogates Cdx4 chromatin access and reduces both active and repressive histone H3 modifications at the Hoxa9 locus; H3K4me3 levels at Hoxa9 correlate with expression levels.","method":"ChIP of Cdx4 and menin at Hoxa9 locus, reporter gene assays, menin ablation with ChIP readout for histone marks","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional reporter, menin ablation experiment, single lab","pmids":["17183676"],"is_preprint":false},{"year":2013,"finding":"HOXA9 binds the CDH3 (P-cadherin) promoter, induces CDH3 expression, and promotes aggregation, anoikis resistance, peritoneal attachment, and migration of ovarian cancer cells; inhibiting P-cadherin abrogates HOXA9-stimulated effects, and reconstituting P-cadherin in HOXA9-inhibited cells restores these effects.","method":"ChIP of HOXA9 at CDH3 promoter, shRNA knockdown, P-cadherin overexpression/inhibition rescue, in vivo xenograft peritoneal model","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, rescue epistasis experiments, in vivo model, single lab","pmids":["25023983"],"is_preprint":false},{"year":2016,"finding":"Chromatin-prebound CRM1 recruits NUP98-HoxA9 to Hox cluster regions; NUP98-HoxA9 forms nuclear aggregates associated with facultative heterochromatin and selectively induces Hox cluster gene expression; leptomycin B (CRM1 inhibitor) disassembles NUP98-HoxA9 nuclear dots and abolishes Hox gene activation.","method":"Genome-wide ChIP-seq of NUP98-HoxA9, leptomycin B treatment, stable expression in mouse ES cells","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus pharmacologic CRM1 inhibition, single lab","pmids":["26740045"],"is_preprint":false},{"year":2017,"finding":"MLL is essential for NUP98-HOXA9-induced leukemia; NUP98-HOXA9 interacts with MLL via the second FG repeat domain of NUP98; in the absence of MLL, NUP98-HOXA9-induced cell immortalization and leukemogenesis are severely inhibited; MLL is required for NUP98-HOXA9 recruitment to the HOXA locus and HOXA gene expression.","method":"Co-immunoprecipitation (NUP98-HOXA9 with MLL), FG repeat domain mutagenesis, MLL conditional knockout in leukemia model, ChIP of NUP98-HOXA9 at HOXA locus","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction (Co-IP) with domain mapping, conditional KO with defined leukemogenesis phenotype and ChIP validation","pmids":["28210005"],"is_preprint":false},{"year":2018,"finding":"HOXA9 functions as a pioneer factor at de novo enhancers during leukemogenesis, recruits C/EBPα and the MLL3/MLL4 complex; genetic deletion of MLL3/MLL4 blocks H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo.","method":"ChIP-seq (HOXA9 enhancer occupancy), MLL3/MLL4 conditional knockout, H3K4me1/H3K27ac profiling, in vivo leukemogenesis assay","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq with pioneer factor evidence, genetic KO of MLL3/MLL4 with in vivo leukemogenesis phenotype, multiple epigenomic readouts","pmids":["30270123"],"is_preprint":false},{"year":2018,"finding":"HOXA9 and STAT5 have genome-wide co-occupancy; co-expression of HOXA9 and mutant JAK3 leads to enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1), accelerating leukemia development from multipotent or lymphoid-committed progenitors.","method":"ChIP-seq, ATAC-seq, RNA-seq in primary mouse cells, mouse leukemia model with JAK3 mutant + HOXA9","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq co-occupancy, ATAC-seq, in vivo leukemia model, multiple orthogonal methods","pmids":["29496663"],"is_preprint":false},{"year":2018,"finding":"HOXA9 inhibits HIF-1α-mediated glycolysis in cutaneous squamous cell carcinoma; mechanistic studies show HOXA9-CRIP2 interaction at glycolytic gene promoters impedes HIF-1α binding and represses HK2, GLUT1, and PDK1 expression in trans.","method":"Co-immunoprecipitation (HOXA9-CRIP2 interaction), ChIP at glycolytic gene promoters, in vitro and xenograft tumor models, HOXA9 overexpression/knockdown","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, in vivo xenograft with defined molecular mechanism, single lab","pmids":["29662084"],"is_preprint":false},{"year":2018,"finding":"HoxA9 drives a positive-feedback loop that enforces expression of the complete HoxA locus and controls oncogenic transcription factors Myc and Myb; HoxA9 directly induces cell cycle regulators Cdk6 and CyclinD1, as well as telomerase; HoxA9 is a substrate for granule proteases (which had confounded prior ChIP-seq in primary cells).","method":"ChIP-seq in protease knockout primary murine cells and human AML line, inducible HoxA9 system, genome-wide enhancer/promoter mapping","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with inducible system for kinetics, single lab, mechanistic pathway placement","pmids":["30463913"],"is_preprint":false},{"year":2019,"finding":"The human HOXA9 protein interacts with TALE cofactors PBX1 and MEIS1 through a combination of the hexapeptide (HX) motif and two paralog-specific residues of the HOXA9 homeodomain; this interaction is context-independent across different DNA-binding sites and cell lines.","method":"Bimolecular Fluorescence Complementation (BiFC) in multiple cell lines, in vitro binding assays on different DNA sites, mutagenesis of HX motif and HD residues","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BiFC and in vitro binding with mutagenesis, multiple cell lines, single lab","pmids":["30952900"],"is_preprint":false},{"year":2013,"finding":"Hoxa9 forms a complex with Roc1-Ddb1-Cul4a ubiquitin ligase and functions as an E3 ubiquitin ligase activator for Geminin; Hoxa9 overexpression or siRNA knockdown respectively down-regulates or up-regulates Geminin protein in hematopoietic cells; Hoxa9-induced repopulating and clonogenic activities are suppressed by Geminin supertransduction.","method":"Co-immunoprecipitation (Hoxa9-Roc1-Ddb1-Cul4a complex), ubiquitylation assay for Geminin, retroviral Hoxa9 transduction, siRNA knockdown, Geminin rescue experiment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex, ubiquitylation assay, functional rescue, single lab","pmids":["23326393"],"is_preprint":false},{"year":2021,"finding":"Trib1 modulates Hoxa9-associated super-enhancers; Trib1 overexpression increases H3K27Ac signals at super-enhancers of Erg, Spns2, Rgl1, and Pik3cd loci, and this is mostly achieved via Trib1-mediated degradation of C/EBPα p42; Erg is a critical downstream target of the Trib1/Hoxa9 axis.","method":"ChIP-seq for H3K27Ac, Erg knockdown, BRD4 inhibitor (JQ1) treatment in vitro and in vivo, Trib1 overexpression in AML cells","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, genetic knockdown with defined downstream target, pharmacologic validation in vivo, single lab","pmids":["32730594"],"is_preprint":false},{"year":2020,"finding":"USF2 directly occupies the HOXA9 promoter in MLL-rearranged leukemia cells (by CUT&RUN analysis) and controls HOXA9 expression; USF2 depletion significantly down-regulates HOXA9 expression and impairs MLLr leukemia cell proliferation; ectopic Hoxa9 expression rescues impaired proliferation upon USF2 loss.","method":"CRISPR/Cas9 screen with HOXA9-mCherry reporter, CUT&RUN (chromatin occupancy), USF2 depletion/rescue experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen, CUT&RUN occupancy at promoter, genetic rescue validating epistasis, multiple orthogonal methods","pmids":["33001025"],"is_preprint":false},{"year":2021,"finding":"Tip60 histone acetyltransferase is recruited by MLL-AF10 and MLL-ENL fusions to the Hoxa9 locus, where it acetylates H2A.Z to promote Hoxa9 gene expression; conditional deletion of Tip60 prevents development of MLL-AF10 and MLL-ENL leukemia.","method":"ChIP of Tip60 at Hoxa9 locus, H2A.Z acetylation assay, conditional Tip60 knockout in leukemia mouse model","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, histone modification assay, conditional KO with in vivo phenotype, single lab","pmids":["33967269"],"is_preprint":false},{"year":2006,"finding":"The NUP98-HOXA9 fusion protein is protected from CUL-4A-mediated ubiquitination and proteasome-dependent degradation (unlike wild-type HOXA9), contributing to protein stabilization; co-expression of C/EBPα with NUP98-HOXA9 reverses the enhanced proliferation of transduced CD34+ cells.","method":"Ubiquitination assay comparing NUP98-HOXA9 vs HOXA9, proteasome inhibition, C/EBPα co-expression rescue in CD34+ cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination comparison assay, functional rescue, single lab","pmids":["17178874"],"is_preprint":false},{"year":2019,"finding":"HOXA9 transcriptionally regulates RELA (the p65 subunit of NF-κB) in cutaneous SCC; loss of HOXA9 upregulates RELA and thus enhances the NF-κB pathway, which in turn transcriptionally promotes anti-apoptotic BCL-XL and autophagic genes ATG1, ATG3, and ATG12.","method":"RNA-seq after HOXA9 knockdown, KEGG pathway analysis, reporter assays, ChIP/promoter analysis for RELA","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — reporter/expression analysis, pathway placement from transcriptomic data, single lab, limited direct mechanistic assay","pmids":["31683603"],"is_preprint":false},{"year":2017,"finding":"TWIST1 forms a complex with WDR5 and lncRNA Hottip, which are members of the MLL/COMPASS-like H3K4 methylase complex; TWIST1 overexpression leads to co-enrichment of TWIST1 and WDR5 at the HOXA9 promoter with increased H3K4me3, dependent on WDR5.","method":"Co-immunoprecipitation (TWIST1-WDR5 complex), ChIP-seq for H3K4me3 at HOXA9 promoter, WDR5 knockdown","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with WDR5-dependent H3K4me3 at HOXA9 promoter, single lab","pmids":["28484075"],"is_preprint":false},{"year":2016,"finding":"DACH1 forms an endogenous complex with HOXA9 (mediated by the DACH1 carboxyl terminus) in t(9;11) leukemia cells; DACH1 has stronger transcription-promoting activity with HOXA9 than does PBX2 with HOXA9.","method":"Co-immunoprecipitation of endogenous HOXA9-DACH1 complex, domain mapping (DACH1 C-terminus), quantitative reporter assay comparison","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, reporter assay comparison, single lab","pmids":["22902925"],"is_preprint":false}],"current_model":"HOXA9 is a homeodomain transcription factor that binds DNA cooperatively with PBX1/2 (requiring the hexapeptide motif and paralog-specific homeodomain residues) and forms trimeric complexes with PBX and MEIS1 on consensus HOX-binding sites to regulate hematopoietic and leukemic gene programs; its activity is modulated post-translationally by PKC-mediated phosphorylation at Ser204/Thr205 (reducing DNA binding), PRMT5-mediated symmetric dimethylation of Arg140 (activating inflammatory gene expression), and CUL-4A-mediated ubiquitylation and proteasomal degradation; as a pioneer factor at de novo enhancers, HOXA9 recruits C/EBPα and the MLL3/MLL4 complex to drive leukemia-specific gene programs; direct transcriptional targets include Pim1, Bcl-2, BRCA1, CDH3 (P-cadherin), TGF-β2, CYBB (gp91Phox), Cdk6, CyclinD1, and the complete HOXA locus; the oncogenic NUP98-HOXA9 fusion protein co-opts CBP/p300 via NUP98 FG repeats and is stabilized against CUL-4A degradation, while MLL protects Hoxa9 CpG clusters from methylation to maintain expression."},"narrative":{"mechanistic_narrative":"HOXA9 is a homeodomain transcription factor that governs hematopoietic and endothelial gene programs and is a central oncogenic driver in acute myeloid leukemia [PMID:9649441, PMID:15928198, PMID:19056693]. It binds DNA cooperatively with the TALE cofactors PBX and MEIS1, forming trimeric complexes through its hexapeptide motif and paralog-specific homeodomain residues; MEIS1 enhances HOXA9-PBX assembly even in the absence of DNA [PMID:10082572, PMID:30952900], and a high-resolution HoxA9-Pbx1-DNA structure shows the posterior hexapeptide adopts an altered conformation conferring stronger affinity and altered specificity [PMID:12923056]. Cofactor selection is functionally decisive: collaboration with MEIS1a transforms primary marrow cells whereas PBX1b does not [PMID:9649441], and PBX3 specifically is the critical cofactor for MLL-fusion leukemogenesis [PMID:23264595]. As a pioneer factor at de novo enhancers, HOXA9 recruits C/EBPalpha and the MLL3/MLL4 H3K4-methyltransferase complex to establish leukemia-specific enhancers, and its genome-wide binding co-occurs with C/EBPalpha and STAT5 [PMID:24958854, PMID:30270123, PMID:29496663]. Through these complexes it directly activates pro-survival and proliferative targets including Pim1 (which inactivates pro-apoptotic BAD), Bcl-2, Cdk6, CyclinD1, and a positive-feedback loop enforcing the complete HoxA locus [PMID:17327400, PMID:24177192, PMID:30463913], while co-repressing the Cdkn2a/b locus to overcome G1 arrest [PMID:24958854]. HOXA9 activity is tuned post-translationally: PKC phosphorylates Ser204/Thr205 to reduce DNA binding [PMID:15082777], PRMT5 symmetrically dimethylates Arg140 to drive inflammatory gene induction [PMID:22269951], and the CUL-4A ubiquitin ligase machinery targets HOXA9 for proteasomal degradation [PMID:14609952]. The t(7;11) translocation fuses the NUP98 N-terminus to the HOXA9 homeodomain, generating an aberrant transcription factor whose FG repeats co-opt CBP/p300 and recruit MLL, which is escape from CUL-4A degradation and chromatin targeting via CRM1 drive Hox-locus activation and transformation [PMID:8563753, PMID:9858599, PMID:28210005, PMID:17178874]. Beyond hematopoiesis, HOXA9 acts as a tumor suppressor in several solid cancers, modulating BRCA1, TGF-beta2, P-cadherin, and HIF-1alpha-driven glycolysis [PMID:20389018, PMID:22945634, PMID:25023983, PMID:29662084].","teleology":[{"year":1996,"claim":"Establishing the molecular structure of a recurrent AML translocation revealed that HOXA9 itself is a target of leukemogenic gene fusion.","evidence":"Translocation mapping and transcript cloning in t(7;11) AML patients","pmids":["8563753"],"confidence":"High","gaps":["Did not establish the transforming mechanism of the fusion","Fusion protein function unaddressed"]},{"year":1998,"claim":"Demonstrating that HOXA9 transforms only in collaboration with MEIS1a and not PBX1b defined cofactor selectivity as the determinant of leukemic transformation.","evidence":"Retroviral overexpression in primary bone marrow and FDC-P1 cells with mouse transplantation","pmids":["9649441"],"confidence":"High","gaps":["Molecular basis of MEIS1a-specific synergy not resolved","Direct target genes not yet identified"]},{"year":1999,"claim":"Biochemical reconstitution showed HOXA9 assembles trimeric complexes with PBX2 and MEIS1, explaining how cofactors stabilize DNA binding, while parallel work dissected how the NUP98-HOXA9 fusion converts these activities into transformation.","evidence":"EMSA, reciprocal co-IP from myeloid nuclear extracts, immunofluorescence; plus NIH 3T3 transformation and CBP/p300 co-IP with domain mutagenesis","pmids":["10082572","9858599"],"confidence":"High","gaps":["In vivo target loci of the trimer not mapped","How FG-repeat coactivator recruitment alters genome-wide targeting unknown"]},{"year":2003,"claim":"A crystal structure plus stability and degradation studies revealed both the structural basis of HOXA9 DNA recognition and that its protein levels are actively controlled by ubiquitin-proteasome turnover.","evidence":"1.9 A X-ray crystallography with DNA-binding mutagenesis; ubiquitylation assay, proteasome inhibition, CUL-4A RNAi and 32D differentiation","pmids":["12923056","14609952"],"confidence":"High","gaps":["The E3 substrate-recognition adaptor for CUL-4A not defined","Signals triggering degradation unknown"]},{"year":2004,"claim":"Identifying PKC phosphorylation of Ser204/Thr205 established a post-translational switch that lowers HOXA9 DNA binding and links it to myeloid differentiation.","evidence":"In vitro kinase assay, site mutagenesis, EMSA, phorbol ester/PKC inhibitor treatment of myeloid cells","pmids":["15082777"],"confidence":"High","gaps":["PKC isoform responsible not specified","In vivo relevance during differentiation not directly tested"]},{"year":2005,"claim":"Functional target studies extended HOXA9 beyond leukemia, defining it as a master regulator of endothelial maturation and a context-dependent activator of myeloid CYBB that the NUP98 fusion subverts.","evidence":"HoxA9 KO mouse with ischemia/neovascularization assay and target-gene readouts; reporter/EMSA promoter studies of CYBB","pmids":["15928198","15681849"],"confidence":"High","gaps":["Cofactor logic distinguishing activation vs repression incompletely mapped","CYBB regulation single-lab reporter evidence"]},{"year":2007,"claim":"Direct ChIP-validated identification of Pim1 as a target connected HOXA9 to suppression of apoptosis via BAD inactivation, providing a survival mechanism for its transforming activity.","evidence":"ChIP, qRT-PCR, Hoxa9-/- cells with Pim1 rescue and BAD phosphorylation readout","pmids":["17327400"],"confidence":"High","gaps":["Cofactor requirements at the Pim1 promoter not defined","Other survival targets not enumerated here"]},{"year":2008,"claim":"Epigenetic and post-transcriptional studies clarified how HOXA9 expression is maintained (MLL protecting CpG clusters from methylation) and limited (miR-126 targeting the homeobox), while RNAi confirmed its requirement in MLL-rearranged leukemia.","evidence":"MLL ChIP with bisulfite sequencing and Mll-null reconstitution; miR-126 reporter and gain/loss assays; RNAi knockdown with in vivo leukemia model","pmids":["18483194","18474618","19056693"],"confidence":"High","gaps":["How MLL excludes the methylation machinery mechanistically unclear","miR-126 evidence single-lab"]},{"year":2010,"claim":"Restoring HOXA9 in breast cancer revealed a tumor-suppressive role mediated through BRCA1, expanding HOXA9 function beyond hematopoiesis into solid-tumor restraint.","evidence":"HOXA9 overexpression/knockdown, xenografts, BRCA1 ectopic rescue epistasis","pmids":["20389018"],"confidence":"Medium","gaps":["Direct vs indirect regulation of BRCA1 not fully resolved","Single-lab finding"]},{"year":2012,"claim":"Distinct cofactor and modification studies defined PBX3 as the leukemia-specific TALE partner, PRMT5 as an inflammatory-activating arginine methyltransferase, and TGF-beta2 as a paracrine target driving the tumor microenvironment.","evidence":"shRNA/co-expression leukemogenesis and HXR9 peptide; MS-identified PRMT5 interaction with Arg140 mutagenesis and ChIP; HOXA9-overexpression fibroblast co-culture and xenografts","pmids":["23264595","22269951","22945634"],"confidence":"High","gaps":["Why PBX3 differs functionally from PBX1/2 at target loci unclear","TGF-beta2 evidence single-lab Medium"]},{"year":2013,"claim":"A cluster of studies mapped the upstream regulators (SALL4/MLL, Cdx4/menin, TET1, USF2) and downstream effectors (Bcl-2 survival, JMJD1C-modulated programs, a Cul4a-Geminin ligase activity) that build the HOXA9 regulatory network.","evidence":"ChIP/co-IP for SALL4-MLL and Cdx4-menin at the Hoxa9 locus; TET1 demethylation ChIP/xenografts; inducible HoxA9 with Bcl-2 KO; JMJD1C co-IP and conditional KO LSC assays; Hoxa9-Roc1-Ddb1-Cul4a complex with Geminin ubiquitylation","pmids":["24051379","17183676","23716660","24177192","26878175","23326393"],"confidence":"High","gaps":["Geminin-ligase activator role single-lab Medium","Integration of multiple upstream activators into a single regulatory logic not established"]},{"year":2014,"claim":"Genome-wide co-occupancy with C/EBPalpha and joint repression of Cdkn2a/b established that HOXA9 and C/EBPalpha cooperate broadly to overcome cell-cycle restraint in leukemia.","evidence":"ChIP-seq co-occupancy, loss-of-function mouse leukemia models, proliferation assays","pmids":["24958854"],"confidence":"High","gaps":["Whether C/EBPalpha is recruited by HOXA9 or vice versa not fully resolved here","Mechanism of Cdkn2a/b co-repression undefined"]},{"year":2016,"claim":"Defining CRM1-mediated chromatin recruitment and DACH1 partnership of the fusion and wild-type proteins added new modes of HOXA9/NUP98-HoxA9 chromatin targeting.","evidence":"ChIP-seq with leptomycin B for NUP98-HoxA9; endogenous HOXA9-DACH1 co-IP with reporter comparison","pmids":["26740045","22902925"],"confidence":"Medium","gaps":["DACH1 interaction is a single low-confidence Co-IP without functional in vivo validation","Mechanism of CRM1-dependent locus selectivity incompletely defined"]},{"year":2017,"claim":"Demonstrating that NUP98-HOXA9 requires MLL for chromatin recruitment and leukemogenesis tied the oncogenic fusion mechanistically to the H3K4 methylation machinery, while TWIST1/WDR5 work showed COMPASS-like recruitment also activates the wild-type HOXA9 promoter.","evidence":"Co-IP with FG-repeat domain mapping, MLL conditional KO, ChIP at HOXA locus; TWIST1-WDR5 co-IP and H3K4me3 ChIP-seq at HOXA9 promoter","pmids":["28210005","28484075"],"confidence":"High","gaps":["Stoichiometry and assembly order of fusion-MLL complex unresolved","TWIST1/WDR5 link single-lab Medium"]},{"year":2018,"claim":"Defining HOXA9 as a pioneer factor at de novo enhancers that recruits MLL3/MLL4 and co-occupies the genome with STAT5, together with a positive-feedback loop enforcing the HoxA locus and cell-cycle/oncogene targets, established the genome-wide architecture of HOXA9-driven leukemia and revealed solid-tumor metabolic roles.","evidence":"ChIP-seq pioneer assays with MLL3/MLL4 KO; HOXA9-STAT5 ChIP/ATAC-seq with JAK3-mutant leukemia model; inducible ChIP-seq feedback mapping; HOXA9-CRIP2 co-IP/ChIP repressing glycolytic genes","pmids":["30270123","29496663","30463913","29662084"],"confidence":"High","gaps":["How HOXA9 accesses closed chromatin as a pioneer factor not mechanistically defined","CRIP2/glycolysis finding single-lab Medium"]},{"year":2020,"claim":"Functional screening identified USF2 as a direct upstream activator of HOXA9 in MLL-rearranged leukemia, validated by rescue, completing a transcriptional dependency map.","evidence":"CRISPR screen with HOXA9 reporter, CUT&RUN occupancy, USF2 depletion with Hoxa9 rescue","pmids":["33001025"],"confidence":"High","gaps":["Whether USF2 cooperates with MLL at the HOXA9 promoter not established","Role outside MLLr leukemia untested"]},{"year":2021,"claim":"Identifying Tip60-mediated H2A.Z acetylation and Trib1-modulated super-enhancers refined the epigenetic mechanisms that sustain Hoxa9 expression and downstream oncogenic targets such as Erg.","evidence":"Tip60 ChIP, H2A.Z acetylation assay and conditional KO; Trib1 H3K27Ac ChIP-seq with Erg knockdown and JQ1 treatment","pmids":["33967269","32730594"],"confidence":"Medium","gaps":["Both are single-lab Medium-confidence findings","Integration with the MLL3/MLL4 enhancer program unresolved"]},{"year":null,"claim":"How HOXA9 selects between transactivation and repression at different loci, and how its pioneer activity opens closed chromatin, remain mechanistically undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of HOXA9 engaging nucleosomal/closed chromatin","Cofactor and post-translational logic distinguishing activator vs repressor states not unified","Substrate spectrum of the proposed Hoxa9-Cul4a ligase activity not broadly mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,9,10,24,29,32]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,6,33]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[34]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,27]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,10,24,29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,15,18,28]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[13,29,37]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,17,6]}],"complexes":["HOXA9-PBX-MEIS1 trimer","MLL3/MLL4 (COMPASS-like) complex","Roc1-Ddb1-Cul4a ubiquitin ligase"],"partners":["PBX1","PBX2","PBX3","MEIS1","CEBPA","PRMT5","JMJD1C","STAT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31269","full_name":"Homeobox protein Hox-A9","aliases":["Homeobox protein Hox-1G"],"length_aa":272,"mass_kda":30.2,"function":"Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Required for induction of SELE/E-selectin and VCAM1 on the endothelial cells surface at sites of inflammation (PubMed:22269951). Positively regulates EIF4E-mediated mRNA nuclear export and also increases the translation efficiency of ODC mRNA in the cytoplasm by competing with factors which repress EIF4E activity such as PRH (By similarity)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P31269/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HOXA9","classification":"Not Classified","n_dependent_lines":47,"n_total_lines":1208,"dependency_fraction":0.03890728476821192},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HOXA9","total_profiled":1310},"omim":[{"mim_id":"614060","title":"HOXA DISTAL TRANSCRIPT ANTISENSE RNA; HOTTIP","url":"https://www.omim.org/entry/614060"},{"mim_id":"613733","title":"MENIN 1; MEN1","url":"https://www.omim.org/entry/613733"},{"mim_id":"610565","title":"DYNEIN, AXONEMAL, LIGHT CHAIN 4; DNAL4","url":"https://www.omim.org/entry/610565"},{"mim_id":"609880","title":"LYSINE ACETYLTRANSFERASE 7; KAT7","url":"https://www.omim.org/entry/609880"},{"mim_id":"608232","title":"LEUKEMIA, CHRONIC MYELOID; CML","url":"https://www.omim.org/entry/608232"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":27.0}],"url":"https://www.proteinatlas.org/search/HOXA9"},"hgnc":{"alias_symbol":[],"prev_symbol":["HOX1G","HOX1"]},"alphafold":{"accession":"P31269","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31269","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31269-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31269-F1-predicted_aligned_error_v6.png","plddt_mean":61.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HOXA9","jax_strain_url":"https://www.jax.org/strain/search?query=HOXA9"},"sequence":{"accession":"P31269","fasta_url":"https://rest.uniprot.org/uniprotkb/P31269.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31269/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31269"}},"corpus_meta":[{"pmid":"9649441","id":"PMC_9649441","title":"Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9649441","citation_count":545,"is_preprint":false},{"pmid":"8563753","id":"PMC_8563753","title":"Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia.","date":"1996","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8563753","citation_count":440,"is_preprint":false},{"pmid":"11756161","id":"PMC_11756161","title":"Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11756161","citation_count":287,"is_preprint":false},{"pmid":"9858599","id":"PMC_9858599","title":"CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity.","date":"1999","source":"Molecular and cellular 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cells, mouse transplantation model, FDC-P1 cell transplantation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined cellular transformation phenotype with genetic epistasis (MEIS1a vs PBX1b), replicated in two cell systems (primary bone marrow and FDC-P1)\",\n      \"pmids\": [\"9649441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The t(7;11)(p15;p15) chromosomal translocation creates an in-frame genomic fusion between HOXA9 and NUP98, generating a chimeric NUP98/HOXA9 transcript containing the NUP98 amino-terminal half fused to the HOXA9 homeodomain.\",\n      \"method\": \"Chromosomal translocation mapping, molecular cloning, transcript analysis in three AML patients\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct molecular identification of fusion gene in three independent patients, foundational structural finding replicated across labs\",\n      \"pmids\": [\"8563753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NUP98-HOXA9 fusion protein acts as an aberrant transcription factor: the NUP98 FG repeats function as potent transactivation domains by physically interacting with coactivators CBP and p300, while the HOXA9 homeodomain provides DNA-binding and PBX heterodimerization; both activities are required for NIH 3T3 transformation.\",\n      \"method\": \"NIH 3T3 transformation assay, transactivation reporter assays, co-immunoprecipitation of CBP/p300 with FG repeats, domain mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro transformation, direct binding (Co-IP), mutagenesis of FG repeats and HOXA9 domains, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9858599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HOXA9 forms trimeric complexes with PBX2 and MEIS1 in myeloid cells: MEIS1 enhances HOXA9-PBX complex formation in the absence of DNA, and the three proteins co-immunoprecipitate from myeloid cell nuclear extracts; co-localization occurs in nuclear speckles.\",\n      \"method\": \"EMSA, DNA site selection, co-immunoprecipitation from myeloid cell nuclear extracts, immunofluorescence co-localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP from nuclear extracts, EMSA trimeric complex, immunofluorescence co-localization, multiple orthogonal methods\",\n      \"pmids\": [\"10082572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of HoxA9 complexed with Pbx1 and DNA at 1.9 Å resolution reveals that the posterior Hox hexapeptide adopts an altered conformation compared to anterior HOX/PBC structures, providing stronger DNA-binding affinity and altered specificity; residues in the N-terminal arm of the homeodomain are critical for DNA sequence recognition through indirect contacts.\",\n      \"method\": \"X-ray crystallography (1.9 Å), DNA-binding mutagenesis of HoxA9 and HoxB1\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional mutagenesis validation, mechanistically definitive\",\n      \"pmids\": [\"12923056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CUL-4A ubiquitylation machinery controls HOXA9 protein stability by promoting its ubiquitylation and proteasome-dependent degradation; the HOXA9 homeodomain is required for CUL-4A-mediated degradation; interference with CUL-4A biosynthesis alters HOXA9 steady-state levels and impairs granulocyte differentiation of 32D myeloid progenitors.\",\n      \"method\": \"Ubiquitylation assay, proteasome inhibition, RNAi knockdown of CUL-4A, ectopic CUL-4A expression, 32D cell differentiation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical ubiquitylation assay, domain mapping (homeodomain required), RNAi + overexpression with defined cellular phenotype\",\n      \"pmids\": [\"14609952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HOXA9 is phosphorylated by protein kinase C (PKC) on Ser204 and Thr205 within the N-terminal region of the homeodomain; PKC-mediated phosphorylation decreases HOXA9 DNA-binding affinity in vitro and reduces cooperative DNA-binding with PBX; PKC inhibition reduces phorbol ester-induced myeloid differentiation, linking HOXA9 phosphorylation to differentiation regulation.\",\n      \"method\": \"In vitro kinase assay with purified HOXA9, site-directed mutagenesis, EMSA, phorbol ester/PKC inhibitor treatment of PLB985 and HOXA9-immortalized murine marrow cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro phosphorylation with site mutagenesis, EMSA functional consequence, cellular phenotype with pharmacologic validation\",\n      \"pmids\": [\"15082777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HOXA9 binds to a Hox binding site in the osteopontin (OPN) promoter and acts as a transcriptional repressor of OPN; Smad4 physically interacts with HOXA9 (co-immunoprecipitation from cotransfected COS-1 cells) and displaces HOXA9 from its cognate DNA site in response to TGF-β stimulation, thereby derepressing OPN transcription.\",\n      \"method\": \"Gel shift (EMSA) with GST-Smad3, co-immunoprecipitation of FLAG-Smad4 with HA-HOXA9, luciferase reporter transfection assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of interaction, EMSA displacement assay, reporter assay; multiple orthogonal methods in single study\",\n      \"pmids\": [\"11042172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HOXA9 activates transcription of the CYBB gene (encoding gp91Phox) in differentiated myeloid cells via a cis-element in the proximal promoter; this activation requires PBX1 and is inhibited by MEIS1; phosphorylation of conserved homeodomain tyrosines increases HOXA9 binding to the CYBB promoter; the NUP98-HOXA9 fusion has greater binding affinity but is unresponsive to tyrosine phosphorylation and blocks CYBB transcription.\",\n      \"method\": \"Reporter gene assays, EMSA, promoter binding studies, phosphorylation assays, expression in myeloid cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays and EMSA in single lab, multiple functional readouts\",\n      \"pmids\": [\"15681849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HDAC activity is required for HoxA9 expression in adult progenitor cells; HoxA9 acts as a master switch to regulate endothelial-committed genes (eNOS, VEGFR2, VE-cadherin) and mediates shear stress-induced endothelial maturation; HoxA9-deficient mice show reduced endothelial progenitor cells and impaired postnatal neovascularization.\",\n      \"method\": \"HDAC inhibitor treatment, HoxA9 overexpression rescue experiments, siRNA knockdown, HoxA9 knockout mouse model with ischemia assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rescue experiment, KO mouse with specific vascular phenotype, knockdown/overexpression with defined target gene readouts\",\n      \"pmids\": [\"15928198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Pim1 kinase is a direct transcriptional target of HOXA9; HOXA9 protein binds the Pim1 promoter and induces Pim1 mRNA and protein in hematopoietic cells; Pim1 induction by HOXA9 increases phosphorylation and inactivation of pro-apoptotic BAD; Hoxa9-/- cells show increased apoptosis and decreased proliferation that are rescued by Pim1 reintroduction.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), quantitative RT-PCR, Western blot, Hoxa9-/- mouse cells, Pim1 rescue experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct promoter binding, KO rescue experiment, BAD phosphorylation mechanistic readout\",\n      \"pmids\": [\"17327400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOXA9 inhibits NF-κB-dependent activation of endothelial cells; HOXA9 overexpression inhibits induction of ICAM-1, VCAM-1, and E-selectin in response to pro-inflammatory cytokines by interfering with NF-κB DNA binding (but not its transactivation capacity or nuclear localization).\",\n      \"method\": \"Luciferase reporter assays with NF-κB-dependent promoters, EMSA for NF-κB DNA binding, HOXA9 overexpression in endothelial cells\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and reporter assays in single lab, mechanistic pathway placement\",\n      \"pmids\": [\"17586512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NF-κB activation is required for HOXA9 transcriptional downregulation during endothelial cell activation; HOXA9 positively autoregulates its own expression requiring both its DNA-binding and transactivation domains.\",\n      \"method\": \"HOXA9 promoter deletion analysis, reporter assays in endothelial cells and NF-κB knockout cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter deletion mapping with reporter assays, NF-κB KO cells as genetic validation, single lab\",\n      \"pmids\": [\"18068911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MLL binds to specific CpG clusters within the Hoxa9 locus and protects them from DNA methylation, thereby maintaining Hoxa9 transcript expression; shRNA knockdown of MLL reverses methylation protection at these CpG clusters; reconstituting MLL expression in Mll-null cells reverses DNA methylation, demonstrating a dominant protective effect.\",\n      \"method\": \"ChIP of MLL at Hoxa9 locus, bisulfite sequencing of CpG methylation, shRNA knockdown of Mll, Mll-null cell reconstitution\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, bisulfite sequencing, shRNA knockdown, and reconstitution in Mll-null cells with multiple orthogonal methods\",\n      \"pmids\": [\"18483194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"miR-126 targets highly conserved sites within the HOXA9 homeobox coding sequence; forced expression of miR-126 downregulates HOXA9 protein and causes loss of biological activity in HOXA9-immortalized bone marrow cells; inhibition of endogenous miR-126 increases HOXA9 protein.\",\n      \"method\": \"Forced miRNA expression, luciferase reporter targeting assays, Western blot for HOXA9 protein, miR-126 inhibitor in F9 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated targeting of homeobox sequence, gain- and loss-of-function, single lab\",\n      \"pmids\": [\"18474618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HOXA9 suppression in MLL-rearranged leukemia cells induces proliferation arrest and apoptosis and co-downregulates HOXA10, MEIS1, PBX3, and MEF2C; HOXA9 depletion reduces leukemia burden in vivo in mice transplanted with t(4;11) SEMK2 cells.\",\n      \"method\": \"RNA interference knockdown, gene expression profiling, apoptosis assays, in vivo mouse leukemia model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi with expression profiling, in vivo xenograft validation, defined apoptosis phenotype\",\n      \"pmids\": [\"19056693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HOXA9 directly modulates BRCA1 expression to restrict breast tumor behavior; restoring HOXA9 expression represses growth and survival of breast cancer cells in culture and xenograft models; wild-type BRCA1 phenocopies HOXA9 tumor suppressor function, and reducing BRCA1 inhibits HOXA9 anti-tumor activity.\",\n      \"method\": \"HOXA9 overexpression and knockdown, xenograft mouse model, molecular correlation studies, BRCA1 ectopic expression rescue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft with rescue experiments, epistasis between HOXA9 and BRCA1, single lab\",\n      \"pmids\": [\"20389018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PRMT5 is a TNF-α-dependent binding partner of HOXA9 (identified by mass spectrometry); PRMT5 induces symmetric dimethylation of Arg140 on HOXA9, which is essential for HOXA9-dependent E-selectin induction; PRMT5 is recruited to the E-selectin promoter following HOXA9 binding; siRNA depletion of PRMT5 abrogates stimulus-dependent HOXA9 methylation and E-selectin/VCAM-1 induction.\",\n      \"method\": \"Mass spectrometry protein identification, Co-IP, siRNA depletion, ChIP, site-directed mutagenesis of Arg140\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — MS-identified interaction, site-specific mutagenesis of methylation site, ChIP, siRNA with defined molecular phenotype\",\n      \"pmids\": [\"22269951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PBX3, but not PBX1 or PBX2, is a critical cofactor of HOXA9 in leukemogenesis; PBX3 depletion significantly inhibits MLL-fusion-mediated cell transformation; co-expressed PBX3 synergizes with HOXA9 in promoting cell transformation in vitro and leukemogenesis in vivo; a peptide (HXR9) disrupting HOX-PBX interactions selectively kills leukemic cells overexpressing HOXA/PBX3.\",\n      \"method\": \"shRNA depletion of PBX3, retroviral co-expression of HOXA9+PBX3, in vivo leukemogenesis mouse model, HXR9 peptide treatment assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function shRNA, gain-of-function co-expression, in vivo leukemogenesis with defined synergistic phenotype\",\n      \"pmids\": [\"23264595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HOXA9 expression in ovarian cancer cells induces normal peritoneal fibroblasts to acquire cancer-associated fibroblast (CAF) markers; these effects are due substantially to HOXA9 transcriptional activation of TGF-β2, which acts in a paracrine manner to induce CXCL12, IL-6, and VEGF-A in fibroblasts/MSCs.\",\n      \"method\": \"HOXA9 overexpression in EOC cells, fibroblast co-culture, xenograft mouse model, TGF-β2 promoter analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft with defined paracrine mechanism via TGF-β2, single lab\",\n      \"pmids\": [\"22945634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HMGA2 depletion induces TET1 expression; TET1 binds and demethylates its own promoter and the HOXA gene promoters (including HOXA9) to enhance HOXA gene expression; both TET1 and HOXA9 suppress breast tumor growth and metastasis in mouse xenografts.\",\n      \"method\": \"ChIP, bisulfite sequencing/methylation analysis, xenograft mouse models, HMGA2 depletion\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for TET1 binding, methylation assay, xenograft with defined signaling pathway, single lab\",\n      \"pmids\": [\"23716660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JMJD1C directly interacts with HOXA9 and modulates a HOXA9-controlled gene-expression program; loss of JMJD1C substantially decreases leukemia stem cell (LSC) frequency and causes differentiation of MLL-AF9- and HOXA9-driven leukemias, while having only minor effects on normal hematopoietic stem cell self-renewal.\",\n      \"method\": \"Co-immunoprecipitation (JMJD1C-HOXA9 interaction), conditional knockout mouse model, in vivo shRNA screen, LSC frequency assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction (Co-IP), conditional KO with defined LSC phenotype, in vivo shRNA screen\",\n      \"pmids\": [\"26878175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HoxA9 maintains Bcl-2 expression in hematopoietic cells; maintenance of HoxA9 overexpression is required for continued cell survival even in the presence of growth factors; hematopoietic cells lacking Bcl-2 are not immortalized by HoxA9 in vitro; deletion of Bcl-2 delays onset and reduces severity of HoxA9/Meis1 and MLL-AF9 leukemias.\",\n      \"method\": \"Inducible HoxA9 system (4-OHT-regulated), Bcl-2 knockout cells, in vivo leukemia mouse model with Bcl-2 deletion\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (Bcl-2 KO in HoxA9 context), in vivo leukemia model with survival readout\",\n      \"pmids\": [\"24177192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SALL4 binds the HOXA9 promoter, and SALL4 overexpression leads to enhanced binding of histone activation markers at the HOXA9 promoter and increased HOXA9 expression; SALL4 co-occupies the HOXA9 promoter with MLL in AML cells (co-immunoprecipitation between SALL4 and MLL), suggesting a SALL4/MLL pathway controlling HOXA9 expression.\",\n      \"method\": \"ChIP of SALL4 at HOXA9 promoter, co-immunoprecipitation of SALL4 and MLL, histone modification ChIP, shRNA knockdown in leukemic cells\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP, single lab, mechanistic pathway placement\",\n      \"pmids\": [\"24051379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"C/EBPα is a critical collaborator required for Hoxa9/Meis1-mediated leukemogenesis; C/EBPα loss greatly improves survival in primary and secondary murine Hoxa9/Meis1 leukemia models; >50% of Hoxa9 genome-wide binding sites are co-occupied by C/EBPα; Hoxa9 and C/EBPα co-repress the Cdkn2a/b locus to overcome G1 cell cycle block.\",\n      \"method\": \"ChIP-seq (genome-wide co-occupancy), loss-of-function mouse models, cell proliferation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq genome-wide co-occupancy, primary and secondary in vivo leukemia models with defined phenotype\",\n      \"pmids\": [\"24958854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cdx4 and menin bind the same regulatory region of the Hoxa9 locus in vivo and co-activate Hoxa9 reporter gene expression; ablation of menin abrogates Cdx4 chromatin access and reduces both active and repressive histone H3 modifications at the Hoxa9 locus; H3K4me3 levels at Hoxa9 correlate with expression levels.\",\n      \"method\": \"ChIP of Cdx4 and menin at Hoxa9 locus, reporter gene assays, menin ablation with ChIP readout for histone marks\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional reporter, menin ablation experiment, single lab\",\n      \"pmids\": [\"17183676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HOXA9 binds the CDH3 (P-cadherin) promoter, induces CDH3 expression, and promotes aggregation, anoikis resistance, peritoneal attachment, and migration of ovarian cancer cells; inhibiting P-cadherin abrogates HOXA9-stimulated effects, and reconstituting P-cadherin in HOXA9-inhibited cells restores these effects.\",\n      \"method\": \"ChIP of HOXA9 at CDH3 promoter, shRNA knockdown, P-cadherin overexpression/inhibition rescue, in vivo xenograft peritoneal model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, rescue epistasis experiments, in vivo model, single lab\",\n      \"pmids\": [\"25023983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Chromatin-prebound CRM1 recruits NUP98-HoxA9 to Hox cluster regions; NUP98-HoxA9 forms nuclear aggregates associated with facultative heterochromatin and selectively induces Hox cluster gene expression; leptomycin B (CRM1 inhibitor) disassembles NUP98-HoxA9 nuclear dots and abolishes Hox gene activation.\",\n      \"method\": \"Genome-wide ChIP-seq of NUP98-HoxA9, leptomycin B treatment, stable expression in mouse ES cells\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus pharmacologic CRM1 inhibition, single lab\",\n      \"pmids\": [\"26740045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MLL is essential for NUP98-HOXA9-induced leukemia; NUP98-HOXA9 interacts with MLL via the second FG repeat domain of NUP98; in the absence of MLL, NUP98-HOXA9-induced cell immortalization and leukemogenesis are severely inhibited; MLL is required for NUP98-HOXA9 recruitment to the HOXA locus and HOXA gene expression.\",\n      \"method\": \"Co-immunoprecipitation (NUP98-HOXA9 with MLL), FG repeat domain mutagenesis, MLL conditional knockout in leukemia model, ChIP of NUP98-HOXA9 at HOXA locus\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction (Co-IP) with domain mapping, conditional KO with defined leukemogenesis phenotype and ChIP validation\",\n      \"pmids\": [\"28210005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HOXA9 functions as a pioneer factor at de novo enhancers during leukemogenesis, recruits C/EBPα and the MLL3/MLL4 complex; genetic deletion of MLL3/MLL4 blocks H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo.\",\n      \"method\": \"ChIP-seq (HOXA9 enhancer occupancy), MLL3/MLL4 conditional knockout, H3K4me1/H3K27ac profiling, in vivo leukemogenesis assay\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq with pioneer factor evidence, genetic KO of MLL3/MLL4 with in vivo leukemogenesis phenotype, multiple epigenomic readouts\",\n      \"pmids\": [\"30270123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HOXA9 and STAT5 have genome-wide co-occupancy; co-expression of HOXA9 and mutant JAK3 leads to enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1), accelerating leukemia development from multipotent or lymphoid-committed progenitors.\",\n      \"method\": \"ChIP-seq, ATAC-seq, RNA-seq in primary mouse cells, mouse leukemia model with JAK3 mutant + HOXA9\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq co-occupancy, ATAC-seq, in vivo leukemia model, multiple orthogonal methods\",\n      \"pmids\": [\"29496663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HOXA9 inhibits HIF-1α-mediated glycolysis in cutaneous squamous cell carcinoma; mechanistic studies show HOXA9-CRIP2 interaction at glycolytic gene promoters impedes HIF-1α binding and represses HK2, GLUT1, and PDK1 expression in trans.\",\n      \"method\": \"Co-immunoprecipitation (HOXA9-CRIP2 interaction), ChIP at glycolytic gene promoters, in vitro and xenograft tumor models, HOXA9 overexpression/knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, in vivo xenograft with defined molecular mechanism, single lab\",\n      \"pmids\": [\"29662084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HoxA9 drives a positive-feedback loop that enforces expression of the complete HoxA locus and controls oncogenic transcription factors Myc and Myb; HoxA9 directly induces cell cycle regulators Cdk6 and CyclinD1, as well as telomerase; HoxA9 is a substrate for granule proteases (which had confounded prior ChIP-seq in primary cells).\",\n      \"method\": \"ChIP-seq in protease knockout primary murine cells and human AML line, inducible HoxA9 system, genome-wide enhancer/promoter mapping\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with inducible system for kinetics, single lab, mechanistic pathway placement\",\n      \"pmids\": [\"30463913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The human HOXA9 protein interacts with TALE cofactors PBX1 and MEIS1 through a combination of the hexapeptide (HX) motif and two paralog-specific residues of the HOXA9 homeodomain; this interaction is context-independent across different DNA-binding sites and cell lines.\",\n      \"method\": \"Bimolecular Fluorescence Complementation (BiFC) in multiple cell lines, in vitro binding assays on different DNA sites, mutagenesis of HX motif and HD residues\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BiFC and in vitro binding with mutagenesis, multiple cell lines, single lab\",\n      \"pmids\": [\"30952900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hoxa9 forms a complex with Roc1-Ddb1-Cul4a ubiquitin ligase and functions as an E3 ubiquitin ligase activator for Geminin; Hoxa9 overexpression or siRNA knockdown respectively down-regulates or up-regulates Geminin protein in hematopoietic cells; Hoxa9-induced repopulating and clonogenic activities are suppressed by Geminin supertransduction.\",\n      \"method\": \"Co-immunoprecipitation (Hoxa9-Roc1-Ddb1-Cul4a complex), ubiquitylation assay for Geminin, retroviral Hoxa9 transduction, siRNA knockdown, Geminin rescue experiment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex, ubiquitylation assay, functional rescue, single lab\",\n      \"pmids\": [\"23326393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Trib1 modulates Hoxa9-associated super-enhancers; Trib1 overexpression increases H3K27Ac signals at super-enhancers of Erg, Spns2, Rgl1, and Pik3cd loci, and this is mostly achieved via Trib1-mediated degradation of C/EBPα p42; Erg is a critical downstream target of the Trib1/Hoxa9 axis.\",\n      \"method\": \"ChIP-seq for H3K27Ac, Erg knockdown, BRD4 inhibitor (JQ1) treatment in vitro and in vivo, Trib1 overexpression in AML cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, genetic knockdown with defined downstream target, pharmacologic validation in vivo, single lab\",\n      \"pmids\": [\"32730594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USF2 directly occupies the HOXA9 promoter in MLL-rearranged leukemia cells (by CUT&RUN analysis) and controls HOXA9 expression; USF2 depletion significantly down-regulates HOXA9 expression and impairs MLLr leukemia cell proliferation; ectopic Hoxa9 expression rescues impaired proliferation upon USF2 loss.\",\n      \"method\": \"CRISPR/Cas9 screen with HOXA9-mCherry reporter, CUT&RUN (chromatin occupancy), USF2 depletion/rescue experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen, CUT&RUN occupancy at promoter, genetic rescue validating epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"33001025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tip60 histone acetyltransferase is recruited by MLL-AF10 and MLL-ENL fusions to the Hoxa9 locus, where it acetylates H2A.Z to promote Hoxa9 gene expression; conditional deletion of Tip60 prevents development of MLL-AF10 and MLL-ENL leukemia.\",\n      \"method\": \"ChIP of Tip60 at Hoxa9 locus, H2A.Z acetylation assay, conditional Tip60 knockout in leukemia mouse model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, histone modification assay, conditional KO with in vivo phenotype, single lab\",\n      \"pmids\": [\"33967269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The NUP98-HOXA9 fusion protein is protected from CUL-4A-mediated ubiquitination and proteasome-dependent degradation (unlike wild-type HOXA9), contributing to protein stabilization; co-expression of C/EBPα with NUP98-HOXA9 reverses the enhanced proliferation of transduced CD34+ cells.\",\n      \"method\": \"Ubiquitination assay comparing NUP98-HOXA9 vs HOXA9, proteasome inhibition, C/EBPα co-expression rescue in CD34+ cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination comparison assay, functional rescue, single lab\",\n      \"pmids\": [\"17178874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HOXA9 transcriptionally regulates RELA (the p65 subunit of NF-κB) in cutaneous SCC; loss of HOXA9 upregulates RELA and thus enhances the NF-κB pathway, which in turn transcriptionally promotes anti-apoptotic BCL-XL and autophagic genes ATG1, ATG3, and ATG12.\",\n      \"method\": \"RNA-seq after HOXA9 knockdown, KEGG pathway analysis, reporter assays, ChIP/promoter analysis for RELA\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reporter/expression analysis, pathway placement from transcriptomic data, single lab, limited direct mechanistic assay\",\n      \"pmids\": [\"31683603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TWIST1 forms a complex with WDR5 and lncRNA Hottip, which are members of the MLL/COMPASS-like H3K4 methylase complex; TWIST1 overexpression leads to co-enrichment of TWIST1 and WDR5 at the HOXA9 promoter with increased H3K4me3, dependent on WDR5.\",\n      \"method\": \"Co-immunoprecipitation (TWIST1-WDR5 complex), ChIP-seq for H3K4me3 at HOXA9 promoter, WDR5 knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with WDR5-dependent H3K4me3 at HOXA9 promoter, single lab\",\n      \"pmids\": [\"28484075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DACH1 forms an endogenous complex with HOXA9 (mediated by the DACH1 carboxyl terminus) in t(9;11) leukemia cells; DACH1 has stronger transcription-promoting activity with HOXA9 than does PBX2 with HOXA9.\",\n      \"method\": \"Co-immunoprecipitation of endogenous HOXA9-DACH1 complex, domain mapping (DACH1 C-terminus), quantitative reporter assay comparison\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, reporter assay comparison, single lab\",\n      \"pmids\": [\"22902925\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOXA9 is a homeodomain transcription factor that binds DNA cooperatively with PBX1/2 (requiring the hexapeptide motif and paralog-specific homeodomain residues) and forms trimeric complexes with PBX and MEIS1 on consensus HOX-binding sites to regulate hematopoietic and leukemic gene programs; its activity is modulated post-translationally by PKC-mediated phosphorylation at Ser204/Thr205 (reducing DNA binding), PRMT5-mediated symmetric dimethylation of Arg140 (activating inflammatory gene expression), and CUL-4A-mediated ubiquitylation and proteasomal degradation; as a pioneer factor at de novo enhancers, HOXA9 recruits C/EBPα and the MLL3/MLL4 complex to drive leukemia-specific gene programs; direct transcriptional targets include Pim1, Bcl-2, BRCA1, CDH3 (P-cadherin), TGF-β2, CYBB (gp91Phox), Cdk6, CyclinD1, and the complete HOXA locus; the oncogenic NUP98-HOXA9 fusion protein co-opts CBP/p300 via NUP98 FG repeats and is stabilized against CUL-4A degradation, while MLL protects Hoxa9 CpG clusters from methylation to maintain expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HOXA9 is a homeodomain transcription factor that governs hematopoietic and endothelial gene programs and is a central oncogenic driver in acute myeloid leukemia [#0, #9, #15]. It binds DNA cooperatively with the TALE cofactors PBX and MEIS1, forming trimeric complexes through its hexapeptide motif and paralog-specific homeodomain residues; MEIS1 enhances HOXA9-PBX assembly even in the absence of DNA [#3, #33], and a high-resolution HoxA9-Pbx1-DNA structure shows the posterior hexapeptide adopts an altered conformation conferring stronger affinity and altered specificity [#4]. Cofactor selection is functionally decisive: collaboration with MEIS1a transforms primary marrow cells whereas PBX1b does not [#0], and PBX3 specifically is the critical cofactor for MLL-fusion leukemogenesis [#18]. As a pioneer factor at de novo enhancers, HOXA9 recruits C/EBPalpha and the MLL3/MLL4 H3K4-methyltransferase complex to establish leukemia-specific enhancers, and its genome-wide binding co-occurs with C/EBPalpha and STAT5 [#24, #29, #30]. Through these complexes it directly activates pro-survival and proliferative targets including Pim1 (which inactivates pro-apoptotic BAD), Bcl-2, Cdk6, CyclinD1, and a positive-feedback loop enforcing the complete HoxA locus [#10, #22, #32], while co-repressing the Cdkn2a/b locus to overcome G1 arrest [#24]. HOXA9 activity is tuned post-translationally: PKC phosphorylates Ser204/Thr205 to reduce DNA binding [#6], PRMT5 symmetrically dimethylates Arg140 to drive inflammatory gene induction [#17], and the CUL-4A ubiquitin ligase machinery targets HOXA9 for proteasomal degradation [#5]. The t(7;11) translocation fuses the NUP98 N-terminus to the HOXA9 homeodomain, generating an aberrant transcription factor whose FG repeats co-opt CBP/p300 and recruit MLL, which is escape from CUL-4A degradation and chromatin targeting via CRM1 drive Hox-locus activation and transformation [#1, #2, #28, #38]. Beyond hematopoiesis, HOXA9 acts as a tumor suppressor in several solid cancers, modulating BRCA1, TGF-beta2, P-cadherin, and HIF-1alpha-driven glycolysis [#16, #19, #26, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the molecular structure of a recurrent AML translocation revealed that HOXA9 itself is a target of leukemogenic gene fusion.\",\n      \"evidence\": \"Translocation mapping and transcript cloning in t(7;11) AML patients\",\n      \"pmids\": [\"8563753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the transforming mechanism of the fusion\", \"Fusion protein function unaddressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that HOXA9 transforms only in collaboration with MEIS1a and not PBX1b defined cofactor selectivity as the determinant of leukemic transformation.\",\n      \"evidence\": \"Retroviral overexpression in primary bone marrow and FDC-P1 cells with mouse transplantation\",\n      \"pmids\": [\"9649441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of MEIS1a-specific synergy not resolved\", \"Direct target genes not yet identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Biochemical reconstitution showed HOXA9 assembles trimeric complexes with PBX2 and MEIS1, explaining how cofactors stabilize DNA binding, while parallel work dissected how the NUP98-HOXA9 fusion converts these activities into transformation.\",\n      \"evidence\": \"EMSA, reciprocal co-IP from myeloid nuclear extracts, immunofluorescence; plus NIH 3T3 transformation and CBP/p300 co-IP with domain mutagenesis\",\n      \"pmids\": [\"10082572\", \"9858599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo target loci of the trimer not mapped\", \"How FG-repeat coactivator recruitment alters genome-wide targeting unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"A crystal structure plus stability and degradation studies revealed both the structural basis of HOXA9 DNA recognition and that its protein levels are actively controlled by ubiquitin-proteasome turnover.\",\n      \"evidence\": \"1.9 A X-ray crystallography with DNA-binding mutagenesis; ubiquitylation assay, proteasome inhibition, CUL-4A RNAi and 32D differentiation\",\n      \"pmids\": [\"12923056\", \"14609952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 substrate-recognition adaptor for CUL-4A not defined\", \"Signals triggering degradation unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying PKC phosphorylation of Ser204/Thr205 established a post-translational switch that lowers HOXA9 DNA binding and links it to myeloid differentiation.\",\n      \"evidence\": \"In vitro kinase assay, site mutagenesis, EMSA, phorbol ester/PKC inhibitor treatment of myeloid cells\",\n      \"pmids\": [\"15082777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PKC isoform responsible not specified\", \"In vivo relevance during differentiation not directly tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Functional target studies extended HOXA9 beyond leukemia, defining it as a master regulator of endothelial maturation and a context-dependent activator of myeloid CYBB that the NUP98 fusion subverts.\",\n      \"evidence\": \"HoxA9 KO mouse with ischemia/neovascularization assay and target-gene readouts; reporter/EMSA promoter studies of CYBB\",\n      \"pmids\": [\"15928198\", \"15681849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactor logic distinguishing activation vs repression incompletely mapped\", \"CYBB regulation single-lab reporter evidence\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Direct ChIP-validated identification of Pim1 as a target connected HOXA9 to suppression of apoptosis via BAD inactivation, providing a survival mechanism for its transforming activity.\",\n      \"evidence\": \"ChIP, qRT-PCR, Hoxa9-/- cells with Pim1 rescue and BAD phosphorylation readout\",\n      \"pmids\": [\"17327400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactor requirements at the Pim1 promoter not defined\", \"Other survival targets not enumerated here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Epigenetic and post-transcriptional studies clarified how HOXA9 expression is maintained (MLL protecting CpG clusters from methylation) and limited (miR-126 targeting the homeobox), while RNAi confirmed its requirement in MLL-rearranged leukemia.\",\n      \"evidence\": \"MLL ChIP with bisulfite sequencing and Mll-null reconstitution; miR-126 reporter and gain/loss assays; RNAi knockdown with in vivo leukemia model\",\n      \"pmids\": [\"18483194\", \"18474618\", \"19056693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MLL excludes the methylation machinery mechanistically unclear\", \"miR-126 evidence single-lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Restoring HOXA9 in breast cancer revealed a tumor-suppressive role mediated through BRCA1, expanding HOXA9 function beyond hematopoiesis into solid-tumor restraint.\",\n      \"evidence\": \"HOXA9 overexpression/knockdown, xenografts, BRCA1 ectopic rescue epistasis\",\n      \"pmids\": [\"20389018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect regulation of BRCA1 not fully resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Distinct cofactor and modification studies defined PBX3 as the leukemia-specific TALE partner, PRMT5 as an inflammatory-activating arginine methyltransferase, and TGF-beta2 as a paracrine target driving the tumor microenvironment.\",\n      \"evidence\": \"shRNA/co-expression leukemogenesis and HXR9 peptide; MS-identified PRMT5 interaction with Arg140 mutagenesis and ChIP; HOXA9-overexpression fibroblast co-culture and xenografts\",\n      \"pmids\": [\"23264595\", \"22269951\", \"22945634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why PBX3 differs functionally from PBX1/2 at target loci unclear\", \"TGF-beta2 evidence single-lab Medium\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A cluster of studies mapped the upstream regulators (SALL4/MLL, Cdx4/menin, TET1, USF2) and downstream effectors (Bcl-2 survival, JMJD1C-modulated programs, a Cul4a-Geminin ligase activity) that build the HOXA9 regulatory network.\",\n      \"evidence\": \"ChIP/co-IP for SALL4-MLL and Cdx4-menin at the Hoxa9 locus; TET1 demethylation ChIP/xenografts; inducible HoxA9 with Bcl-2 KO; JMJD1C co-IP and conditional KO LSC assays; Hoxa9-Roc1-Ddb1-Cul4a complex with Geminin ubiquitylation\",\n      \"pmids\": [\"24051379\", \"17183676\", \"23716660\", \"24177192\", \"26878175\", \"23326393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Geminin-ligase activator role single-lab Medium\", \"Integration of multiple upstream activators into a single regulatory logic not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genome-wide co-occupancy with C/EBPalpha and joint repression of Cdkn2a/b established that HOXA9 and C/EBPalpha cooperate broadly to overcome cell-cycle restraint in leukemia.\",\n      \"evidence\": \"ChIP-seq co-occupancy, loss-of-function mouse leukemia models, proliferation assays\",\n      \"pmids\": [\"24958854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether C/EBPalpha is recruited by HOXA9 or vice versa not fully resolved here\", \"Mechanism of Cdkn2a/b co-repression undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining CRM1-mediated chromatin recruitment and DACH1 partnership of the fusion and wild-type proteins added new modes of HOXA9/NUP98-HoxA9 chromatin targeting.\",\n      \"evidence\": \"ChIP-seq with leptomycin B for NUP98-HoxA9; endogenous HOXA9-DACH1 co-IP with reporter comparison\",\n      \"pmids\": [\"26740045\", \"22902925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DACH1 interaction is a single low-confidence Co-IP without functional in vivo validation\", \"Mechanism of CRM1-dependent locus selectivity incompletely defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that NUP98-HOXA9 requires MLL for chromatin recruitment and leukemogenesis tied the oncogenic fusion mechanistically to the H3K4 methylation machinery, while TWIST1/WDR5 work showed COMPASS-like recruitment also activates the wild-type HOXA9 promoter.\",\n      \"evidence\": \"Co-IP with FG-repeat domain mapping, MLL conditional KO, ChIP at HOXA locus; TWIST1-WDR5 co-IP and H3K4me3 ChIP-seq at HOXA9 promoter\",\n      \"pmids\": [\"28210005\", \"28484075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of fusion-MLL complex unresolved\", \"TWIST1/WDR5 link single-lab Medium\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining HOXA9 as a pioneer factor at de novo enhancers that recruits MLL3/MLL4 and co-occupies the genome with STAT5, together with a positive-feedback loop enforcing the HoxA locus and cell-cycle/oncogene targets, established the genome-wide architecture of HOXA9-driven leukemia and revealed solid-tumor metabolic roles.\",\n      \"evidence\": \"ChIP-seq pioneer assays with MLL3/MLL4 KO; HOXA9-STAT5 ChIP/ATAC-seq with JAK3-mutant leukemia model; inducible ChIP-seq feedback mapping; HOXA9-CRIP2 co-IP/ChIP repressing glycolytic genes\",\n      \"pmids\": [\"30270123\", \"29496663\", \"30463913\", \"29662084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HOXA9 accesses closed chromatin as a pioneer factor not mechanistically defined\", \"CRIP2/glycolysis finding single-lab Medium\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Functional screening identified USF2 as a direct upstream activator of HOXA9 in MLL-rearranged leukemia, validated by rescue, completing a transcriptional dependency map.\",\n      \"evidence\": \"CRISPR screen with HOXA9 reporter, CUT&RUN occupancy, USF2 depletion with Hoxa9 rescue\",\n      \"pmids\": [\"33001025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USF2 cooperates with MLL at the HOXA9 promoter not established\", \"Role outside MLLr leukemia untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying Tip60-mediated H2A.Z acetylation and Trib1-modulated super-enhancers refined the epigenetic mechanisms that sustain Hoxa9 expression and downstream oncogenic targets such as Erg.\",\n      \"evidence\": \"Tip60 ChIP, H2A.Z acetylation assay and conditional KO; Trib1 H3K27Ac ChIP-seq with Erg knockdown and JQ1 treatment\",\n      \"pmids\": [\"33967269\", \"32730594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both are single-lab Medium-confidence findings\", \"Integration with the MLL3/MLL4 enhancer program unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HOXA9 selects between transactivation and repression at different loci, and how its pioneer activity opens closed chromatin, remain mechanistically undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of HOXA9 engaging nucleosomal/closed chromatin\", \"Cofactor and post-translational logic distinguishing activator vs repressor states not unified\", \"Substrate spectrum of the proposed Hoxa9-Cul4a ligase activity not broadly mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 9, 10, 24, 29, 32]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 6, 33]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [34]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 27]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 10, 24, 29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 15, 18, 28]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [13, 29, 37]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 17, 6]}\n    ],\n    \"complexes\": [\n      \"HOXA9-PBX-MEIS1 trimer\",\n      \"MLL3/MLL4 (COMPASS-like) complex\",\n      \"Roc1-Ddb1-Cul4a ubiquitin ligase\"\n    ],\n    \"partners\": [\n      \"PBX1\",\n      \"PBX2\",\n      \"PBX3\",\n      \"MEIS1\",\n      \"CEBPA\",\n      \"PRMT5\",\n      \"JMJD1C\",\n      \"STAT5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}