{"gene":"CDX4","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2003,"finding":"cdx4 (kugelig locus in zebrafish) is required for specification of haematopoietic progenitors by regulating hox gene expression; the haematopoietic defect in cdx4 mutants is rescued by overexpression of hoxb7a or hoxa9a but not hoxb8a, and is not rescued by scl overexpression, placing cdx4 upstream of specific hox genes but parallel to scl in making posterior mesoderm competent for blood development. Overexpression of cdx4 in zebrafish or mouse ES cells induces blood formation.","method":"Genetic screen (zebrafish kugelig mutant), rescue experiments with hox gene overexpression, scl overexpression epistasis, cdx4 overexpression in zebrafish and mouse ES cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic epistasis with multiple rescues, replicated across two model systems, highly cited foundational paper","pmids":["13679919"],"is_preprint":false},{"year":1993,"finding":"Murine Cdx-4 protein and mRNA are expressed in a posterior-to-anterior gradient during gastrulation (7.0–10 d.p.c.), localizing to the allantois, primitive streak, neurectoderm, presomitic and lateral plate mesoderm, and hindgut endoderm, consistent with a role in anteroposterior axial patterning.","method":"In situ hybridization and immunohistochemistry in mouse embryos","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by two orthogonal methods, single lab","pmids":["7902125"],"is_preprint":false},{"year":2005,"finding":"Cdx4 is a direct transcriptional target of the canonical Wnt pathway; LEF1 and β-catenin bind the Cdx4 promoter at LEF/TCF response elements, and Cdx4 expression is down-regulated in Wnt3a mutant embryos and by Wnt inhibitors.","method":"Chromatin immunoprecipitation (ChIP) from embryocarcinoma cells and embryo tail buds, promoter-reporter assays in P19 cells, ex vivo embryo culture with Wnt3a/inhibitors, Wnt3a mutant analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP in two biological contexts plus promoter mutagenesis and in vivo genetic validation","pmids":["16309666"],"is_preprint":false},{"year":2005,"finding":"Cdx4 and cdx2 proteins form posterior-to-anterior gradients during gastrulation by protein decay as cells move away from the regressing tailbud; an enhancer in the first intron of the cdx4 gene is essential for correct transgene expression.","method":"lacZ reporter transgenic mouse embryos, in situ hybridization","journal":"The International journal of developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional enhancer element identified, single lab","pmids":["16281167"],"is_preprint":false},{"year":2006,"finding":"Cdx4 contributes redundantly with Cdx1 and Cdx2 to anteroposterior vertebral patterning and axial elongation in mice; combined inactivation of Cdx4 with heterozygous Cdx2 loss causes placental labyrinth defects, including failure of allantoic vascular network extension into chorionic ectoderm.","method":"Targeted knockout of mouse Cdx4; compound mutant analysis (Cdx1/Cdx4, Cdx2/Cdx4 double mutants)","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined compound-mutant phenotypes, multiple allelic combinations","pmids":["16396910"],"is_preprint":false},{"year":2006,"finding":"Cdx4 and menin both bind to the same regulatory region of the Hoxa9 locus in hematopoietic cells and co-activate a Hoxa9 reporter. Menin is required for Cdx4 chromatin access; menin ablation abrogates Cdx4 binding to the Hoxa9 locus and reduces both active (H3K4me3) and repressive histone H3 modifications there.","method":"Chromatin immunoprecipitation (ChIP), reporter co-activation assays, menin knockdown/ablation in hematopoietic cells, histone modification analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP with functional reporter validation and loss-of-function epistasis, multiple orthogonal methods","pmids":["17183676"],"is_preprint":false},{"year":2008,"finding":"cdx4 functions cell-autonomously within the endoderm to confer posterior identity, localizing the pancreas, liver, and small intestine; cdx4 may block pancreatic identity by preventing retinoic acid signal transduction in posterior endoderm.","method":"Zebrafish cdx4 morpholino knockdown, tissue-specific cdx4 morpholino in endoderm, endoderm-specific cdx4 overexpression, RA treatment epistasis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — cell-autonomous rescue/overexpression experiments with specific phenotypic readouts, multiple orthogonal approaches","pmids":["18234725"],"is_preprint":false},{"year":2010,"finding":"Cdx4 is a direct transcriptional target of Cdx2; Cdx2 binds Cdx response elements in the Cdx4 promoter (verified by EMSA and ChIP from embryos) and activates Cdx4 transcription independently of canonical Wnt signaling.","method":"Promoter-reporter assays, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation from embryos, Cdx2 knockout analysis","journal":"Mechanisms of development","confidence":"High","confidence_rationale":"Tier 1-2 — EMSA plus in vivo ChIP plus in vivo genetic data, multiple orthogonal methods","pmids":["20933081"],"is_preprint":false},{"year":2010,"finding":"Cdx4 is dispensable for establishment and maintenance of adult mammalian hematopoiesis under homeostatic conditions, but promotes MLL-AF9-mediated acute myeloid leukemia; loss of Cdx4 significantly delayed MLL-AF9-induced AML in a retroviral bone marrow transplant model.","method":"Germline and conditional Cdx4 knockout mice, competitive transplantation assays, MLL-AF9 retroviral transduction/bone marrow transplant leukemia model","journal":"Haematologica","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined cellular and in vivo phenotypes, multiple experimental approaches","pmids":["20494928"],"is_preprint":false},{"year":2011,"finding":"HoxA10 and Cdx4 form a positive transcriptional feedback loop in myeloid cells: HoxA10 binds a cis element in the CDX4 promoter to activate transcription, and Cdx4 binds a cis element in the HOXA10 promoter to activate transcription. Cdx4 influences transcription of HoxA10 target genes in a HoxA10-dependent manner, and knockdown of Cdx4 decreases cytokine hypersensitivity of HoxA10-overexpressing cells.","method":"Promoter-reporter assays with cis-element mapping, ChIP, Cdx4 knockdown in myeloid progenitor cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — bidirectional promoter binding validated by ChIP and reporter assays plus functional knockdown, multiple orthogonal methods","pmids":["21471217"],"is_preprint":false},{"year":2011,"finding":"Tcf3 represses cdx4 expression by directly binding multiple sites in the cdx4 gene regulatory region in cooperation with Groucho/TLE and HDAC1 corepressors. The transcription factor E4f1 derepresses cdx4 by dissociating corepressors from Tcf3 (without disrupting Tcf3 DNA binding), while E3 ubiquitin ligase Lnx2b acts as a scaffold to counteract E4f1.","method":"Zebrafish embryo and cultured mammalian cell assays, ChIP, protein interaction studies, functional rescue experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — mechanism dissected in two biological systems with ChIP and protein interaction data, multiple orthogonal methods","pmids":["21666599"],"is_preprint":false},{"year":2012,"finding":"β-catenin directly binds novel cis elements in the CDX4 and HOXA10 promoters in myeloid progenitor cells, identifying both as β-catenin target genes. HoxA10-induced CDX4 transcription is augmented by Fgf2-dependent β-catenin activation, and Cdx4-induced HOXA10 transcription is similarly influenced by β-catenin in an Fgf2-dependent manner.","method":"Promoter-reporter assays with cis-element identification, ChIP for β-catenin occupancy, Fgf2 treatment and inhibition in myeloid progenitor cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus promoter mapping plus functional assays, multiple orthogonal methods","pmids":["23038246"],"is_preprint":false},{"year":2013,"finding":"ChIP-seq identified sall4 as a direct Cdx4 target gene; Sall4 in turn binds its own gene locus and the cdx4 locus (auto- and cross-regulation). Cdx4 and Sall4 co-regulate hematopoiesis-initiating genes (hox, scl, lmo2); combined cdx4/sall4 knockdown impairs erythropoiesis, rescued by co-overexpression of scl and lmo2.","method":"ChIP-seq and gene expression profiling in zebrafish, double knockdown, overexpression rescue experiments","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide ChIP-seq plus expression profiling plus genetic epistasis with rescue, multiple orthogonal methods","pmids":["24286030"],"is_preprint":false},{"year":2014,"finding":"HoxA9 represses CDX4 transcription in differentiating myeloid cells, antagonizing HoxA10-mediated activation. Tyrosine phosphorylation of HoxA10 impairs CDX4 activation, while tyrosine phosphorylation of HoxA9 facilitates CDX4 repression, providing a differentiation stage-specific mechanism. Constitutively active Shp2 blocks cytokine-induced phosphorylation of HoxA9/HoxA10, sustaining CDX4 transcription in leukemia.","method":"Promoter-reporter assays, phosphorylation site mutagenesis, Mll-Ell and constitutively active Shp2 co-expression in myeloid progenitor cells","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection with mutagenesis and multiple genetic perturbations, multiple orthogonal approaches","pmids":["25531430"],"is_preprint":false},{"year":2015,"finding":"Cdx4 differentially regulates hox gene transcription in a paralogous group-dependent manner in zebrafish: it primarily controls the timing of hox gene transcriptional activation (initiation phase) in trunk neural and mesodermal tissues, with distinct effects on head (group 4) and tail (group 11-13) hox genes.","method":"Spatiotemporal in situ hybridization of all 49 zebrafish hox genes in wild-type vs. Cdx4-deficient embryos","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — comprehensive loss-of-function analysis with defined molecular readout, single lab","pmids":["26335559"],"is_preprint":false},{"year":2016,"finding":"Cdx4 suppresses expression of the RA-degrading enzyme Cyp26a1 in the presumptive spinal cord, thereby preventing RA degradation in that domain. Conversely, RA signaling activates cyp26a1 and inhibits cdx4 expansion in the hindbrain. These reciprocal interactions between Cdx4 and RA/Cyp26a1 position the hindbrain-spinal cord boundary.","method":"Chemical inhibitors of RA signaling, morpholino knockdown of Cdx4, in situ hybridization for boundary markers in zebrafish","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and morpholino perturbations with defined molecular and anatomical phenotypes, single lab","pmids":["26773000"],"is_preprint":false},{"year":2017,"finding":"CDX4 is expressed exclusively in definitive hematopoietic KDR+CD235a- mesoderm in a WNT- and FGF-dependent manner in human PSC differentiation. Exogenous CDX4 expression during mesoderm specification represses primitive hematopoietic potential (>90%) and confers definitive hematopoietic potential; CDX4 knockout hPSCs have intact primitive but fivefold reduced definitive hematopoietic potential.","method":"Stage-specific hPSC differentiation, whole-transcriptome analysis, CDX4 overexpression, CDX4 knockout hPSCs, flow cytometry with CD235a/KDR markers","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — both gain- and loss-of-function in human cells with defined lineage phenotypes and molecular context","pmids":["28408465"],"is_preprint":false},{"year":2019,"finding":"CDX4 is a dual-function core component of the gene regulatory network controlling spinal cord neural progenitor maturation in chicken: CDX4 simultaneously represses the early neural differentiation marker Nkx1.2 and promotes the late neural differentiation marker Pax6, and prevents premature PAX6-dependent neural differentiation by blocking Ngn2 activation. This CDX4 regulation of Pax6 is restricted to the rostral pre-neural tube by Retinoic Acid signaling.","method":"Chicken pre-neural tube gain- and loss-of-function experiments, in situ hybridization, expression marker analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — loss- and gain-of-function with defined molecular targets in a model organism, single lab","pmids":["30825428"],"is_preprint":false},{"year":2019,"finding":"Aberrant expression of Cdx4 in mice induces transplantable acute erythroid leukemia by upregulating stemness/leukemogenesis genes while downregulating Gata1/Gata2 erythroid differentiation target genes; Cdx4 induces a proteomic profile overlapping with primitive human erythroid progenitors.","method":"Retroviral Cdx4 overexpression in mouse bone marrow transplant model, gene expression profiling, proteomics, whole-exome sequencing of leukemic mice","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 — in vivo overexpression model with transcriptomic, proteomic, and genomic validation","pmids":["31770439"],"is_preprint":false},{"year":2021,"finding":"Zebrafish Cdx4 is expressed in trunk neural crest (NC) cell progenitors, directly binds NC cell-specific enhancers in the NC gene regulatory network, and regulates expression of foxd3 in the posterior body. Cdx4 mutants show disrupted segmental trunk NC cell migration (loss of leader/follower dynamics); cell transplantation demonstrated that Cdx4 functions cell-autonomously in NC cells rather than in the adjacent paraxial mesoderm.","method":"ChIP for enhancer binding, morpholino/mutant analysis, in situ hybridization, cell transplantation chimera experiments in zebrafish","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — direct ChIP evidence for enhancer binding plus cell-autonomous function established by transplantation, multiple orthogonal methods","pmids":["34389276"],"is_preprint":false},{"year":2005,"finding":"A consensus Oct1 binding site in the proximal Xenopus Cdx4 promoter (63 bp region) is required for posterior promoter activity; Oct1 co-expression activates a Cdx4 reporter, and mutation of the octamer site abolishes activity. This octamer site is conserved in human, mouse, chicken, and zebrafish Cdx4 promoters.","method":"Transgenic reporter assays in Xenopus, deletion analysis, co-expression with Oct1, octamer site mutagenesis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 1-2 — promoter mutagenesis with in vivo reporter validation, conserved element","pmids":["15950614"],"is_preprint":false}],"current_model":"CDX4 is a caudal-type homeodomain transcription factor that functions downstream of canonical Wnt (and Fgf) signaling—via direct LEF/TCF-mediated and Cdx2-mediated promoter activation—and upstream of specific Hox genes (including Hoxa9/Hoxa10) and co-regulators such as Sall4 and menin, to confer posterior positional identity in mesoderm, endoderm, and neural tissues; it is required for definitive (but not primitive) hematopoietic specification, endodermal organ positioning, placental labyrinth formation, and neural progenitor maturation, and its aberrant sustained expression—amplified through a HoxA10/Cdx4/β-catenin positive feedback loop—promotes acute myeloid and erythroid leukemogenesis."},"narrative":{"teleology":[{"year":1993,"claim":"Establishing where and when CDX4 is expressed resolved its candidacy as a posterior patterning factor: CDX4 mRNA and protein form a posterior-to-anterior gradient across gastrulation-stage mesoderm, neurectoderm, and hindgut endoderm.","evidence":"In situ hybridization and immunohistochemistry in mouse embryos (7.0–10 d.p.c.)","pmids":["7902125"],"confidence":"Medium","gaps":["Expression pattern alone does not prove function","No loss-of-function data at this stage"]},{"year":2003,"claim":"The first functional demonstration that CDX4 is required for hematopoietic specification showed it acts upstream of specific Hox genes (hoxa9a, hoxb7a) but parallel to scl, placing it as a Hox-dependent posteriorizing signal rather than a direct hematopoietic transcription factor.","evidence":"Zebrafish kugelig mutant genetic screen, Hox rescue epistasis, cdx4 overexpression in zebrafish and mouse ES cells","pmids":["13679919"],"confidence":"High","gaps":["Which Hox targets are direct versus indirect was unknown","Upstream signals activating Cdx4 were unresolved"]},{"year":2005,"claim":"Identifying canonical Wnt signaling as a direct upstream activator of CDX4—via LEF1/β-catenin occupancy of the Cdx4 promoter—and discovering that an Oct1-dependent octamer element and an intronic enhancer control posterior expression established the transcriptional input logic of the Cdx4 locus.","evidence":"ChIP from embryocarcinoma cells and embryo tailbuds, promoter-reporter mutagenesis, Wnt3a mutant analysis, Xenopus transgenic reporter assays with Oct1 co-expression","pmids":["16309666","15950614","16281167"],"confidence":"High","gaps":["Relative contributions of Wnt vs. Oct1 vs. enhancer inputs were not quantified","Whether FGF acts on the Cdx4 promoter directly was not tested"]},{"year":2006,"claim":"Compound Cdx-family knockout mice revealed that CDX4 contributes redundantly with CDX1/CDX2 to vertebral patterning and axial elongation, and uniquely with CDX2 to placental labyrinth vascularization, defining its non-redundant developmental roles.","evidence":"Targeted Cdx4 knockout, Cdx1/Cdx4 and Cdx2/Cdx4 compound mutant mice","pmids":["16396910"],"confidence":"High","gaps":["Molecular targets mediating placental defect were not identified","Single Cdx4 KO has mild phenotype, complicating assignment of specific functions"]},{"year":2006,"claim":"Demonstrating that CDX4 and menin co-occupy the Hoxa9 locus and that menin is required for CDX4 chromatin access revealed a chromatin-gating mechanism for CDX4-dependent Hox activation in hematopoietic cells.","evidence":"ChIP, reporter co-activation assays, menin ablation with histone modification analysis in hematopoietic cells","pmids":["17183676"],"confidence":"High","gaps":["Whether menin-dependent access applies to all CDX4 target loci was not tested","Structural basis of CDX4–menin interaction unknown"]},{"year":2008,"claim":"Cell-autonomous endodermal function of CDX4 was demonstrated: CDX4 confers posterior identity within endoderm to position pancreas, liver, and intestine, partly by opposing retinoic acid signal transduction.","evidence":"Endoderm-specific cdx4 morpholino knockdown and overexpression, RA treatment epistasis in zebrafish","pmids":["18234725"],"confidence":"High","gaps":["Direct transcriptional targets in endoderm not identified","Mechanism of RA signal blockade by CDX4 not resolved"]},{"year":2010,"claim":"Two key advances clarified CDX4's regulatory hierarchy: CDX2 directly activates CDX4 transcription independently of Wnt signaling, and CDX4 is dispensable for normal adult hematopoiesis yet promotes MLL-AF9–driven acute myeloid leukemia in vivo.","evidence":"EMSA plus in vivo ChIP from embryos for Cdx2→Cdx4 regulation; germline and conditional Cdx4 KO mice with competitive transplantation and MLL-AF9 retroviral leukemia model","pmids":["20933081","20494928"],"confidence":"High","gaps":["How CDX4 supports MLL-AF9 leukemogenesis mechanistically was not defined","Cdx2→Cdx4 regulation not tested in hematopoietic context"]},{"year":2011,"claim":"Discovery of a HoxA10↔CDX4 positive transcriptional feedback loop, together with Tcf3/Groucho/HDAC1-mediated repression of cdx4 that is relieved by E4f1, defined how CDX4 expression is both sustained in leukemia and repressed during normal patterning.","evidence":"Bidirectional ChIP and promoter-reporter mapping in myeloid progenitors; ChIP for Tcf3/corepressors and E4f1 derepression in zebrafish and mammalian cells","pmids":["21471217","21666599"],"confidence":"High","gaps":["Whether Tcf3-mediated repression operates in hematopoietic cells was not tested","Relative strength of HoxA10 activation vs. HoxA9 repression of CDX4 during differentiation was not quantified"]},{"year":2012,"claim":"β-catenin directly occupies both the CDX4 and HOXA10 promoters in myeloid progenitors and amplifies the HoxA10/CDX4 feedback loop in an FGF2-dependent manner, integrating Wnt and FGF inputs into leukemogenic transcriptional circuitry.","evidence":"ChIP for β-catenin occupancy, promoter-reporter cis-element mapping, FGF2 treatment/inhibition in myeloid progenitor cells","pmids":["23038246"],"confidence":"High","gaps":["In vivo significance of FGF2-dependent loop amplification in leukemia patients not established","Whether additional Wnt ligands substitute for FGF2 was not tested"]},{"year":2013,"claim":"Genome-wide identification of CDX4 targets by ChIP-seq revealed Sall4 as a direct target; CDX4 and Sall4 cross-regulate each other and co-activate hematopoietic genes (scl, lmo2), with combined loss impairing erythropoiesis rescued by scl/lmo2 co-overexpression.","evidence":"ChIP-seq and expression profiling in zebrafish, double knockdown, overexpression rescue","pmids":["24286030"],"confidence":"High","gaps":["Whether CDX4–Sall4 cross-regulation occurs in mammalian hematopoiesis was not tested","Full target overlap between CDX4 and Sall4 not functionally validated"]},{"year":2014,"claim":"Differentiation stage–specific regulation of CDX4 was resolved: HoxA9 represses CDX4 in differentiating myeloid cells (opposing HoxA10 activation), and tyrosine phosphorylation of HoxA9/HoxA10 switches this balance; constitutively active Shp2 blocks this phosphorylation, sustaining CDX4 in leukemia.","evidence":"Phosphorylation site mutagenesis, promoter-reporter assays, Mll-Ell and constitutively active Shp2 co-expression in myeloid progenitors","pmids":["25531430"],"confidence":"High","gaps":["Identity of the kinase(s) phosphorylating HoxA9/HoxA10 at the relevant tyrosines not determined","Whether Shp2 mutations in human AML sustain CDX4 not validated"]},{"year":2015,"claim":"Comprehensive Hox expression profiling in Cdx4-deficient zebrafish showed CDX4 primarily controls the timing of Hox transcriptional initiation in a paralog group–dependent manner, distinguishing its role from simple on/off regulation.","evidence":"Spatiotemporal in situ hybridization of all 49 zebrafish hox genes in wild-type vs. Cdx4-deficient embryos","pmids":["26335559"],"confidence":"Medium","gaps":["Mechanism by which CDX4 differentially times distinct paralog groups is unknown","Single lab, awaits independent confirmation"]},{"year":2016,"claim":"Reciprocal inhibition between CDX4 and retinoic acid/Cyp26a1 was shown to position the hindbrain–spinal cord boundary: CDX4 suppresses Cyp26a1 posteriorly while RA inhibits cdx4 rostrally.","evidence":"Chemical RA inhibitors, morpholino knockdown, in situ hybridization for boundary markers in zebrafish","pmids":["26773000"],"confidence":"Medium","gaps":["Whether CDX4 directly represses cyp26a1 transcription or acts indirectly is unresolved","Single lab, morpholino-based"]},{"year":2017,"claim":"In human PSC differentiation, CDX4 was shown to be expressed exclusively in definitive hematopoietic mesoderm and to be both necessary and sufficient to specify definitive over primitive hematopoiesis, translating zebrafish findings to the human system.","evidence":"Stage-specific hPSC differentiation, CDX4 overexpression and knockout hPSCs, flow cytometry with CD235a/KDR lineage markers","pmids":["28408465"],"confidence":"High","gaps":["Downstream transcriptional program in human definitive progenitors not fully mapped","Whether CDX4 is sufficient for engraftable definitive HSCs not tested"]},{"year":2019,"claim":"Two new functional domains of CDX4 were defined: it drives transplantable acute erythroid leukemia via stemness gene upregulation and GATA1/2 suppression, and it acts as a dual-function regulator in spinal cord neural progenitors by simultaneously repressing Nkx1.2 and activating Pax6 while preventing premature neuronal differentiation.","evidence":"Retroviral Cdx4 overexpression in mouse bone marrow transplant model with transcriptomic/proteomic profiling; chicken pre-neural tube gain- and loss-of-function with marker analysis","pmids":["31770439","30825428"],"confidence":"High","gaps":["Direct versus indirect regulation of GATA1/2 by CDX4 not distinguished","Neural progenitor targets identified only in chicken; mammalian conservation not tested"]},{"year":2021,"claim":"CDX4 was found to function cell-autonomously in trunk neural crest cells, directly binding NC-specific enhancers to regulate foxd3 and control segmental NC migration, expanding CDX4's role beyond mesoderm and endoderm patterning.","evidence":"ChIP for enhancer binding, mutant analysis, cell transplantation chimera experiments in zebrafish","pmids":["34389276"],"confidence":"High","gaps":["Full set of CDX4-bound NC enhancers not catalogued genome-wide","Whether CDX4 regulates NC in amniotes not established"]},{"year":null,"claim":"Key unresolved questions include the structural basis of CDX4–menin and CDX4–cofactor interactions, whether CDX4 mutations directly cause human Mendelian disease or contribute to human AML, and how CDX4's dual activating/repressing functions are mechanistically switched at different genomic targets.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of CDX4 or its complexes","No human genetic disease directly attributed to CDX4 mutations","Genome-wide binding data in mammalian hematopoietic or neural progenitors lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,5,9,12,19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,6,9,12,14,17,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5,9,12]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,4,6,14,15,17,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,7,9,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,18]}],"complexes":[],"partners":["MENIN","SALL4","HOXA10","HOXA9","LEF1","CTNNB1","TCF3","CDX2"],"other_free_text":[]},"mechanistic_narrative":"CDX4 is a caudal-type homeodomain transcription factor that operates downstream of canonical Wnt/β-catenin and FGF signaling to establish posterior positional identity in mesoderm, endoderm, and neural tissues during vertebrate embryogenesis [PMID:16309666, PMID:28408465, PMID:7902125]. CDX4 directly activates specific Hox genes (notably Hoxa9 and Hoxa10) in concert with the chromatin co-regulator menin and the zinc-finger factor Sall4, and it controls the timing of Hox transcriptional initiation in a paralog group–dependent manner to pattern the anteroposterior axis, specify definitive (but not primitive) hematopoietic progenitors, position endodermal organs, and regulate spinal cord neural progenitor maturation [PMID:13679919, PMID:17183676, PMID:24286030, PMID:26335559, PMID:6773000, PMID:30825428]. CDX4 participates in a positive transcriptional feedback loop with HoxA10 and β-catenin in myeloid progenitors; sustained aberrant expression of CDX4—maintained, for example, by constitutively active Shp2 or MLL fusion oncoproteins—drives acute myeloid and erythroid leukemogenesis by upregulating stemness genes while suppressing GATA1/GATA2-dependent erythroid differentiation [PMID:21471217, PMID:23038246, PMID:25531430, PMID:31770439, PMID:20494928]. CDX4 also acts cell-autonomously in trunk neural crest cells, directly binding neural-crest enhancers to regulate foxd3 expression and segmental migration [PMID:34389276]."},"prefetch_data":{"uniprot":{"accession":"O14627","full_name":"Homeobox protein CDX-4","aliases":["Caudal-type homeobox protein 4"],"length_aa":284,"mass_kda":30.5,"function":"","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O14627/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDX4","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDX4","total_profiled":1310},"omim":[{"mim_id":"608964","title":"TATA BOX-BINDING PROTEIN-LIKE PROTEIN 2; TBPL2","url":"https://www.omim.org/entry/608964"},{"mim_id":"600297","title":"CAUDAL-TYPE HOMEOBOX TRANSCRIPTION FACTOR 2; CDX2","url":"https://www.omim.org/entry/600297"},{"mim_id":"300922","title":"CYSTEINE-RICH HYDROPHOBIC DOMAIN PROTEIN 1; CHIC1","url":"https://www.omim.org/entry/300922"},{"mim_id":"300026","title":"NUCLEOSOME ASSEMBLY PROTEIN 1-LIKE 2; NAP1L2","url":"https://www.omim.org/entry/300026"},{"mim_id":"300025","title":"CAUDAL-TYPE HOMEOBOX TRANSCRIPTION FACTOR 4; CDX4","url":"https://www.omim.org/entry/300025"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"skin 1","ntpm":1.0}],"url":"https://www.proteinatlas.org/search/CDX4"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O14627","domains":[{"cath_id":"1.10.10.60","chopping":"179-242","consensus_level":"medium","plddt":94.9158,"start":179,"end":242}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14627","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14627-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14627-F1-predicted_aligned_error_v6.png","plddt_mean":61.78},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDX4","jax_strain_url":"https://www.jax.org/strain/search?query=CDX4"},"sequence":{"accession":"O14627","fasta_url":"https://rest.uniprot.org/uniprotkb/O14627.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14627/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14627"}},"corpus_meta":[{"pmid":"13679919","id":"PMC_13679919","title":"cdx4 mutants fail to specify blood progenitors and can be rescued by multiple hox genes.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/13679919","citation_count":201,"is_preprint":false},{"pmid":"7902125","id":"PMC_7902125","title":"Murine Cdx-4 bears striking similarities to the Drosophila caudal gene in its homeodomain sequence and early expression pattern.","date":"1993","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/7902125","citation_count":151,"is_preprint":false},{"pmid":"16396910","id":"PMC_16396910","title":"The Cdx4 mutation affects axial development and reveals an essential role of Cdx genes in the ontogenesis of the placental labyrinth in mice.","date":"2006","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16396910","citation_count":94,"is_preprint":false},{"pmid":"16309666","id":"PMC_16309666","title":"Cdx4 is a direct target of the canonical Wnt pathway.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16309666","citation_count":89,"is_preprint":false},{"pmid":"18234725","id":"PMC_18234725","title":"Cdx4 is required in the endoderm to localize the pancreas and limit beta-cell number.","date":"2008","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18234725","citation_count":45,"is_preprint":false},{"pmid":"19301404","id":"PMC_19301404","title":"Overlapping functions of Cdx1, Cdx2, and Cdx4 in the development of the amphibian Xenopus tropicalis.","date":"2009","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/19301404","citation_count":40,"is_preprint":false},{"pmid":"16281167","id":"PMC_16281167","title":"cdx4/lacZ and cdx2/lacZ protein gradients formed by decay during gastrulation in the mouse.","date":"2005","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16281167","citation_count":29,"is_preprint":false},{"pmid":"24286030","id":"PMC_24286030","title":"A Cdx4-Sall4 regulatory module controls the transition from mesoderm formation to embryonic hematopoiesis.","date":"2013","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24286030","citation_count":29,"is_preprint":false},{"pmid":"20415644","id":"PMC_20415644","title":"A chemical genetic screen in zebrafish for pathways interacting with cdx4 in primitive hematopoiesis.","date":"2010","source":"Zebrafish","url":"https://pubmed.ncbi.nlm.nih.gov/20415644","citation_count":28,"is_preprint":false},{"pmid":"17183676","id":"PMC_17183676","title":"Cdx4 and menin co-regulate Hoxa9 expression in hematopoietic cells.","date":"2006","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/17183676","citation_count":27,"is_preprint":false},{"pmid":"21471217","id":"PMC_21471217","title":"HoxA10 activates CDX4 transcription and Cdx4 activates HOXA10 transcription in myeloid cells.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21471217","citation_count":23,"is_preprint":false},{"pmid":"21666599","id":"PMC_21666599","title":"Modulation of Tcf3 repressor complex composition regulates cdx4 expression in zebrafish.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21666599","citation_count":22,"is_preprint":false},{"pmid":"28408465","id":"PMC_28408465","title":"Human definitive hematopoietic specification from pluripotent stem cells is regulated by mesodermal expression of CDX4.","date":"2017","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/28408465","citation_count":20,"is_preprint":false},{"pmid":"20933081","id":"PMC_20933081","title":"Cdx4 is a Cdx2 target gene.","date":"2010","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/20933081","citation_count":15,"is_preprint":false},{"pmid":"26335559","id":"PMC_26335559","title":"Spatiotemporal analysis of zebrafish hox gene regulation by Cdx4.","date":"2015","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/26335559","citation_count":15,"is_preprint":false},{"pmid":"23038246","id":"PMC_23038246","title":"β-Catenin activates the HOXA10 and CDX4 genes in myeloid progenitor cells.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23038246","citation_count":15,"is_preprint":false},{"pmid":"26773000","id":"PMC_26773000","title":"CDX4 and retinoic acid interact to position the hindbrain-spinal cord transition.","date":"2016","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/26773000","citation_count":15,"is_preprint":false},{"pmid":"25531430","id":"PMC_25531430","title":"Regulation of CDX4 gene transcription by HoxA9, HoxA10, the Mll-Ell oncogene and Shp2 during leukemogenesis.","date":"2014","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25531430","citation_count":13,"is_preprint":false},{"pmid":"36552416","id":"PMC_36552416","title":"Chicken LEAP2 Level Substantially Changes with Feed Intake and May Be Regulated by CDX4 in Small Intestine.","date":"2022","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/36552416","citation_count":13,"is_preprint":false},{"pmid":"20494928","id":"PMC_20494928","title":"Cdx4 is dispensable for murine adult hematopoietic stem cells but promotes MLL-AF9-mediated leukemogenesis.","date":"2010","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/20494928","citation_count":13,"is_preprint":false},{"pmid":"30825428","id":"PMC_30825428","title":"CDX4 regulates the progression of neural maturation in the spinal cord.","date":"2019","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/30825428","citation_count":10,"is_preprint":false},{"pmid":"15950614","id":"PMC_15950614","title":"A consensus Oct1 binding site is required for the activity of the Xenopus Cdx4 promoter.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15950614","citation_count":7,"is_preprint":false},{"pmid":"25401498","id":"PMC_25401498","title":"Spatiotemporal expression of Cdx4 in the developing anorectum of rat embryos with ethylenethiourea-induced anorectal malformations.","date":"2014","source":"Cells, tissues, organs","url":"https://pubmed.ncbi.nlm.nih.gov/25401498","citation_count":6,"is_preprint":false},{"pmid":"31770439","id":"PMC_31770439","title":"The ParaHox gene Cdx4 induces acute erythroid leukemia in mice.","date":"2019","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/31770439","citation_count":4,"is_preprint":false},{"pmid":"34389276","id":"PMC_34389276","title":"Zebrafish Cdx4 regulates neural crest cell specification and migratory behaviors in the posterior body.","date":"2021","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34389276","citation_count":3,"is_preprint":false},{"pmid":"35569347","id":"PMC_35569347","title":"CD1d expression demarcates CDX4+ hemogenic mesoderm with definitive hematopoietic potential.","date":"2022","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35569347","citation_count":1,"is_preprint":false},{"pmid":"17196761","id":"PMC_17196761","title":"Ex vivo expanding hematopoietic stem cells by intracellular delivery of Cdx4 fusion proteins.","date":"2006","source":"Medical hypotheses","url":"https://pubmed.ncbi.nlm.nih.gov/17196761","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13987,"output_tokens":5211,"usd":0.060063},"stage2":{"model":"claude-opus-4-6","input_tokens":8756,"output_tokens":4204,"usd":0.22332},"total_usd":0.283383,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"cdx4 (kugelig locus in zebrafish) is required for specification of haematopoietic progenitors by regulating hox gene expression; the haematopoietic defect in cdx4 mutants is rescued by overexpression of hoxb7a or hoxa9a but not hoxb8a, and is not rescued by scl overexpression, placing cdx4 upstream of specific hox genes but parallel to scl in making posterior mesoderm competent for blood development. Overexpression of cdx4 in zebrafish or mouse ES cells induces blood formation.\",\n      \"method\": \"Genetic screen (zebrafish kugelig mutant), rescue experiments with hox gene overexpression, scl overexpression epistasis, cdx4 overexpression in zebrafish and mouse ES cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic epistasis with multiple rescues, replicated across two model systems, highly cited foundational paper\",\n      \"pmids\": [\"13679919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Murine Cdx-4 protein and mRNA are expressed in a posterior-to-anterior gradient during gastrulation (7.0–10 d.p.c.), localizing to the allantois, primitive streak, neurectoderm, presomitic and lateral plate mesoderm, and hindgut endoderm, consistent with a role in anteroposterior axial patterning.\",\n      \"method\": \"In situ hybridization and immunohistochemistry in mouse embryos\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by two orthogonal methods, single lab\",\n      \"pmids\": [\"7902125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cdx4 is a direct transcriptional target of the canonical Wnt pathway; LEF1 and β-catenin bind the Cdx4 promoter at LEF/TCF response elements, and Cdx4 expression is down-regulated in Wnt3a mutant embryos and by Wnt inhibitors.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) from embryocarcinoma cells and embryo tail buds, promoter-reporter assays in P19 cells, ex vivo embryo culture with Wnt3a/inhibitors, Wnt3a mutant analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP in two biological contexts plus promoter mutagenesis and in vivo genetic validation\",\n      \"pmids\": [\"16309666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cdx4 and cdx2 proteins form posterior-to-anterior gradients during gastrulation by protein decay as cells move away from the regressing tailbud; an enhancer in the first intron of the cdx4 gene is essential for correct transgene expression.\",\n      \"method\": \"lacZ reporter transgenic mouse embryos, in situ hybridization\",\n      \"journal\": \"The International journal of developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional enhancer element identified, single lab\",\n      \"pmids\": [\"16281167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cdx4 contributes redundantly with Cdx1 and Cdx2 to anteroposterior vertebral patterning and axial elongation in mice; combined inactivation of Cdx4 with heterozygous Cdx2 loss causes placental labyrinth defects, including failure of allantoic vascular network extension into chorionic ectoderm.\",\n      \"method\": \"Targeted knockout of mouse Cdx4; compound mutant analysis (Cdx1/Cdx4, Cdx2/Cdx4 double mutants)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined compound-mutant phenotypes, multiple allelic combinations\",\n      \"pmids\": [\"16396910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cdx4 and menin both bind to the same regulatory region of the Hoxa9 locus in hematopoietic cells and co-activate a Hoxa9 reporter. Menin is required for Cdx4 chromatin access; menin ablation abrogates Cdx4 binding to the Hoxa9 locus and reduces both active (H3K4me3) and repressive histone H3 modifications there.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), reporter co-activation assays, menin knockdown/ablation in hematopoietic cells, histone modification analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP with functional reporter validation and loss-of-function epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"17183676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"cdx4 functions cell-autonomously within the endoderm to confer posterior identity, localizing the pancreas, liver, and small intestine; cdx4 may block pancreatic identity by preventing retinoic acid signal transduction in posterior endoderm.\",\n      \"method\": \"Zebrafish cdx4 morpholino knockdown, tissue-specific cdx4 morpholino in endoderm, endoderm-specific cdx4 overexpression, RA treatment epistasis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-autonomous rescue/overexpression experiments with specific phenotypic readouts, multiple orthogonal approaches\",\n      \"pmids\": [\"18234725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cdx4 is a direct transcriptional target of Cdx2; Cdx2 binds Cdx response elements in the Cdx4 promoter (verified by EMSA and ChIP from embryos) and activates Cdx4 transcription independently of canonical Wnt signaling.\",\n      \"method\": \"Promoter-reporter assays, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation from embryos, Cdx2 knockout analysis\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — EMSA plus in vivo ChIP plus in vivo genetic data, multiple orthogonal methods\",\n      \"pmids\": [\"20933081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cdx4 is dispensable for establishment and maintenance of adult mammalian hematopoiesis under homeostatic conditions, but promotes MLL-AF9-mediated acute myeloid leukemia; loss of Cdx4 significantly delayed MLL-AF9-induced AML in a retroviral bone marrow transplant model.\",\n      \"method\": \"Germline and conditional Cdx4 knockout mice, competitive transplantation assays, MLL-AF9 retroviral transduction/bone marrow transplant leukemia model\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined cellular and in vivo phenotypes, multiple experimental approaches\",\n      \"pmids\": [\"20494928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HoxA10 and Cdx4 form a positive transcriptional feedback loop in myeloid cells: HoxA10 binds a cis element in the CDX4 promoter to activate transcription, and Cdx4 binds a cis element in the HOXA10 promoter to activate transcription. Cdx4 influences transcription of HoxA10 target genes in a HoxA10-dependent manner, and knockdown of Cdx4 decreases cytokine hypersensitivity of HoxA10-overexpressing cells.\",\n      \"method\": \"Promoter-reporter assays with cis-element mapping, ChIP, Cdx4 knockdown in myeloid progenitor cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional promoter binding validated by ChIP and reporter assays plus functional knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"21471217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Tcf3 represses cdx4 expression by directly binding multiple sites in the cdx4 gene regulatory region in cooperation with Groucho/TLE and HDAC1 corepressors. The transcription factor E4f1 derepresses cdx4 by dissociating corepressors from Tcf3 (without disrupting Tcf3 DNA binding), while E3 ubiquitin ligase Lnx2b acts as a scaffold to counteract E4f1.\",\n      \"method\": \"Zebrafish embryo and cultured mammalian cell assays, ChIP, protein interaction studies, functional rescue experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanism dissected in two biological systems with ChIP and protein interaction data, multiple orthogonal methods\",\n      \"pmids\": [\"21666599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"β-catenin directly binds novel cis elements in the CDX4 and HOXA10 promoters in myeloid progenitor cells, identifying both as β-catenin target genes. HoxA10-induced CDX4 transcription is augmented by Fgf2-dependent β-catenin activation, and Cdx4-induced HOXA10 transcription is similarly influenced by β-catenin in an Fgf2-dependent manner.\",\n      \"method\": \"Promoter-reporter assays with cis-element identification, ChIP for β-catenin occupancy, Fgf2 treatment and inhibition in myeloid progenitor cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus promoter mapping plus functional assays, multiple orthogonal methods\",\n      \"pmids\": [\"23038246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ChIP-seq identified sall4 as a direct Cdx4 target gene; Sall4 in turn binds its own gene locus and the cdx4 locus (auto- and cross-regulation). Cdx4 and Sall4 co-regulate hematopoiesis-initiating genes (hox, scl, lmo2); combined cdx4/sall4 knockdown impairs erythropoiesis, rescued by co-overexpression of scl and lmo2.\",\n      \"method\": \"ChIP-seq and gene expression profiling in zebrafish, double knockdown, overexpression rescue experiments\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide ChIP-seq plus expression profiling plus genetic epistasis with rescue, multiple orthogonal methods\",\n      \"pmids\": [\"24286030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HoxA9 represses CDX4 transcription in differentiating myeloid cells, antagonizing HoxA10-mediated activation. Tyrosine phosphorylation of HoxA10 impairs CDX4 activation, while tyrosine phosphorylation of HoxA9 facilitates CDX4 repression, providing a differentiation stage-specific mechanism. Constitutively active Shp2 blocks cytokine-induced phosphorylation of HoxA9/HoxA10, sustaining CDX4 transcription in leukemia.\",\n      \"method\": \"Promoter-reporter assays, phosphorylation site mutagenesis, Mll-Ell and constitutively active Shp2 co-expression in myeloid progenitor cells\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with mutagenesis and multiple genetic perturbations, multiple orthogonal approaches\",\n      \"pmids\": [\"25531430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cdx4 differentially regulates hox gene transcription in a paralogous group-dependent manner in zebrafish: it primarily controls the timing of hox gene transcriptional activation (initiation phase) in trunk neural and mesodermal tissues, with distinct effects on head (group 4) and tail (group 11-13) hox genes.\",\n      \"method\": \"Spatiotemporal in situ hybridization of all 49 zebrafish hox genes in wild-type vs. Cdx4-deficient embryos\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive loss-of-function analysis with defined molecular readout, single lab\",\n      \"pmids\": [\"26335559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cdx4 suppresses expression of the RA-degrading enzyme Cyp26a1 in the presumptive spinal cord, thereby preventing RA degradation in that domain. Conversely, RA signaling activates cyp26a1 and inhibits cdx4 expansion in the hindbrain. These reciprocal interactions between Cdx4 and RA/Cyp26a1 position the hindbrain-spinal cord boundary.\",\n      \"method\": \"Chemical inhibitors of RA signaling, morpholino knockdown of Cdx4, in situ hybridization for boundary markers in zebrafish\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and morpholino perturbations with defined molecular and anatomical phenotypes, single lab\",\n      \"pmids\": [\"26773000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDX4 is expressed exclusively in definitive hematopoietic KDR+CD235a- mesoderm in a WNT- and FGF-dependent manner in human PSC differentiation. Exogenous CDX4 expression during mesoderm specification represses primitive hematopoietic potential (>90%) and confers definitive hematopoietic potential; CDX4 knockout hPSCs have intact primitive but fivefold reduced definitive hematopoietic potential.\",\n      \"method\": \"Stage-specific hPSC differentiation, whole-transcriptome analysis, CDX4 overexpression, CDX4 knockout hPSCs, flow cytometry with CD235a/KDR markers\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — both gain- and loss-of-function in human cells with defined lineage phenotypes and molecular context\",\n      \"pmids\": [\"28408465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDX4 is a dual-function core component of the gene regulatory network controlling spinal cord neural progenitor maturation in chicken: CDX4 simultaneously represses the early neural differentiation marker Nkx1.2 and promotes the late neural differentiation marker Pax6, and prevents premature PAX6-dependent neural differentiation by blocking Ngn2 activation. This CDX4 regulation of Pax6 is restricted to the rostral pre-neural tube by Retinoic Acid signaling.\",\n      \"method\": \"Chicken pre-neural tube gain- and loss-of-function experiments, in situ hybridization, expression marker analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss- and gain-of-function with defined molecular targets in a model organism, single lab\",\n      \"pmids\": [\"30825428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Aberrant expression of Cdx4 in mice induces transplantable acute erythroid leukemia by upregulating stemness/leukemogenesis genes while downregulating Gata1/Gata2 erythroid differentiation target genes; Cdx4 induces a proteomic profile overlapping with primitive human erythroid progenitors.\",\n      \"method\": \"Retroviral Cdx4 overexpression in mouse bone marrow transplant model, gene expression profiling, proteomics, whole-exome sequencing of leukemic mice\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo overexpression model with transcriptomic, proteomic, and genomic validation\",\n      \"pmids\": [\"31770439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Zebrafish Cdx4 is expressed in trunk neural crest (NC) cell progenitors, directly binds NC cell-specific enhancers in the NC gene regulatory network, and regulates expression of foxd3 in the posterior body. Cdx4 mutants show disrupted segmental trunk NC cell migration (loss of leader/follower dynamics); cell transplantation demonstrated that Cdx4 functions cell-autonomously in NC cells rather than in the adjacent paraxial mesoderm.\",\n      \"method\": \"ChIP for enhancer binding, morpholino/mutant analysis, in situ hybridization, cell transplantation chimera experiments in zebrafish\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct ChIP evidence for enhancer binding plus cell-autonomous function established by transplantation, multiple orthogonal methods\",\n      \"pmids\": [\"34389276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A consensus Oct1 binding site in the proximal Xenopus Cdx4 promoter (63 bp region) is required for posterior promoter activity; Oct1 co-expression activates a Cdx4 reporter, and mutation of the octamer site abolishes activity. This octamer site is conserved in human, mouse, chicken, and zebrafish Cdx4 promoters.\",\n      \"method\": \"Transgenic reporter assays in Xenopus, deletion analysis, co-expression with Oct1, octamer site mutagenesis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — promoter mutagenesis with in vivo reporter validation, conserved element\",\n      \"pmids\": [\"15950614\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDX4 is a caudal-type homeodomain transcription factor that functions downstream of canonical Wnt (and Fgf) signaling—via direct LEF/TCF-mediated and Cdx2-mediated promoter activation—and upstream of specific Hox genes (including Hoxa9/Hoxa10) and co-regulators such as Sall4 and menin, to confer posterior positional identity in mesoderm, endoderm, and neural tissues; it is required for definitive (but not primitive) hematopoietic specification, endodermal organ positioning, placental labyrinth formation, and neural progenitor maturation, and its aberrant sustained expression—amplified through a HoxA10/Cdx4/β-catenin positive feedback loop—promotes acute myeloid and erythroid leukemogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDX4 is a caudal-type homeodomain transcription factor that operates downstream of canonical Wnt/β-catenin and FGF signaling to establish posterior positional identity in mesoderm, endoderm, and neural tissues during vertebrate embryogenesis [PMID:16309666, PMID:28408465, PMID:7902125]. CDX4 directly activates specific Hox genes (notably Hoxa9 and Hoxa10) in concert with the chromatin co-regulator menin and the zinc-finger factor Sall4, and it controls the timing of Hox transcriptional initiation in a paralog group–dependent manner to pattern the anteroposterior axis, specify definitive (but not primitive) hematopoietic progenitors, position endodermal organs, and regulate spinal cord neural progenitor maturation [PMID:13679919, PMID:17183676, PMID:24286030, PMID:26335559, PMID:6773000, PMID:30825428]. CDX4 participates in a positive transcriptional feedback loop with HoxA10 and β-catenin in myeloid progenitors; sustained aberrant expression of CDX4—maintained, for example, by constitutively active Shp2 or MLL fusion oncoproteins—drives acute myeloid and erythroid leukemogenesis by upregulating stemness genes while suppressing GATA1/GATA2-dependent erythroid differentiation [PMID:21471217, PMID:23038246, PMID:25531430, PMID:31770439, PMID:20494928]. CDX4 also acts cell-autonomously in trunk neural crest cells, directly binding neural-crest enhancers to regulate foxd3 expression and segmental migration [PMID:34389276].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing where and when CDX4 is expressed resolved its candidacy as a posterior patterning factor: CDX4 mRNA and protein form a posterior-to-anterior gradient across gastrulation-stage mesoderm, neurectoderm, and hindgut endoderm.\",\n      \"evidence\": \"In situ hybridization and immunohistochemistry in mouse embryos (7.0–10 d.p.c.)\",\n      \"pmids\": [\"7902125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Expression pattern alone does not prove function\", \"No loss-of-function data at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The first functional demonstration that CDX4 is required for hematopoietic specification showed it acts upstream of specific Hox genes (hoxa9a, hoxb7a) but parallel to scl, placing it as a Hox-dependent posteriorizing signal rather than a direct hematopoietic transcription factor.\",\n      \"evidence\": \"Zebrafish kugelig mutant genetic screen, Hox rescue epistasis, cdx4 overexpression in zebrafish and mouse ES cells\",\n      \"pmids\": [\"13679919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which Hox targets are direct versus indirect was unknown\", \"Upstream signals activating Cdx4 were unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying canonical Wnt signaling as a direct upstream activator of CDX4—via LEF1/β-catenin occupancy of the Cdx4 promoter—and discovering that an Oct1-dependent octamer element and an intronic enhancer control posterior expression established the transcriptional input logic of the Cdx4 locus.\",\n      \"evidence\": \"ChIP from embryocarcinoma cells and embryo tailbuds, promoter-reporter mutagenesis, Wnt3a mutant analysis, Xenopus transgenic reporter assays with Oct1 co-expression\",\n      \"pmids\": [\"16309666\", \"15950614\", \"16281167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of Wnt vs. Oct1 vs. enhancer inputs were not quantified\", \"Whether FGF acts on the Cdx4 promoter directly was not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Compound Cdx-family knockout mice revealed that CDX4 contributes redundantly with CDX1/CDX2 to vertebral patterning and axial elongation, and uniquely with CDX2 to placental labyrinth vascularization, defining its non-redundant developmental roles.\",\n      \"evidence\": \"Targeted Cdx4 knockout, Cdx1/Cdx4 and Cdx2/Cdx4 compound mutant mice\",\n      \"pmids\": [\"16396910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets mediating placental defect were not identified\", \"Single Cdx4 KO has mild phenotype, complicating assignment of specific functions\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that CDX4 and menin co-occupy the Hoxa9 locus and that menin is required for CDX4 chromatin access revealed a chromatin-gating mechanism for CDX4-dependent Hox activation in hematopoietic cells.\",\n      \"evidence\": \"ChIP, reporter co-activation assays, menin ablation with histone modification analysis in hematopoietic cells\",\n      \"pmids\": [\"17183676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether menin-dependent access applies to all CDX4 target loci was not tested\", \"Structural basis of CDX4–menin interaction unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Cell-autonomous endodermal function of CDX4 was demonstrated: CDX4 confers posterior identity within endoderm to position pancreas, liver, and intestine, partly by opposing retinoic acid signal transduction.\",\n      \"evidence\": \"Endoderm-specific cdx4 morpholino knockdown and overexpression, RA treatment epistasis in zebrafish\",\n      \"pmids\": [\"18234725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets in endoderm not identified\", \"Mechanism of RA signal blockade by CDX4 not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Two key advances clarified CDX4's regulatory hierarchy: CDX2 directly activates CDX4 transcription independently of Wnt signaling, and CDX4 is dispensable for normal adult hematopoiesis yet promotes MLL-AF9–driven acute myeloid leukemia in vivo.\",\n      \"evidence\": \"EMSA plus in vivo ChIP from embryos for Cdx2→Cdx4 regulation; germline and conditional Cdx4 KO mice with competitive transplantation and MLL-AF9 retroviral leukemia model\",\n      \"pmids\": [\"20933081\", \"20494928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDX4 supports MLL-AF9 leukemogenesis mechanistically was not defined\", \"Cdx2→Cdx4 regulation not tested in hematopoietic context\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery of a HoxA10↔CDX4 positive transcriptional feedback loop, together with Tcf3/Groucho/HDAC1-mediated repression of cdx4 that is relieved by E4f1, defined how CDX4 expression is both sustained in leukemia and repressed during normal patterning.\",\n      \"evidence\": \"Bidirectional ChIP and promoter-reporter mapping in myeloid progenitors; ChIP for Tcf3/corepressors and E4f1 derepression in zebrafish and mammalian cells\",\n      \"pmids\": [\"21471217\", \"21666599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Tcf3-mediated repression operates in hematopoietic cells was not tested\", \"Relative strength of HoxA10 activation vs. HoxA9 repression of CDX4 during differentiation was not quantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"β-catenin directly occupies both the CDX4 and HOXA10 promoters in myeloid progenitors and amplifies the HoxA10/CDX4 feedback loop in an FGF2-dependent manner, integrating Wnt and FGF inputs into leukemogenic transcriptional circuitry.\",\n      \"evidence\": \"ChIP for β-catenin occupancy, promoter-reporter cis-element mapping, FGF2 treatment/inhibition in myeloid progenitor cells\",\n      \"pmids\": [\"23038246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of FGF2-dependent loop amplification in leukemia patients not established\", \"Whether additional Wnt ligands substitute for FGF2 was not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genome-wide identification of CDX4 targets by ChIP-seq revealed Sall4 as a direct target; CDX4 and Sall4 cross-regulate each other and co-activate hematopoietic genes (scl, lmo2), with combined loss impairing erythropoiesis rescued by scl/lmo2 co-overexpression.\",\n      \"evidence\": \"ChIP-seq and expression profiling in zebrafish, double knockdown, overexpression rescue\",\n      \"pmids\": [\"24286030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDX4–Sall4 cross-regulation occurs in mammalian hematopoiesis was not tested\", \"Full target overlap between CDX4 and Sall4 not functionally validated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Differentiation stage–specific regulation of CDX4 was resolved: HoxA9 represses CDX4 in differentiating myeloid cells (opposing HoxA10 activation), and tyrosine phosphorylation of HoxA9/HoxA10 switches this balance; constitutively active Shp2 blocks this phosphorylation, sustaining CDX4 in leukemia.\",\n      \"evidence\": \"Phosphorylation site mutagenesis, promoter-reporter assays, Mll-Ell and constitutively active Shp2 co-expression in myeloid progenitors\",\n      \"pmids\": [\"25531430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase(s) phosphorylating HoxA9/HoxA10 at the relevant tyrosines not determined\", \"Whether Shp2 mutations in human AML sustain CDX4 not validated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Comprehensive Hox expression profiling in Cdx4-deficient zebrafish showed CDX4 primarily controls the timing of Hox transcriptional initiation in a paralog group–dependent manner, distinguishing its role from simple on/off regulation.\",\n      \"evidence\": \"Spatiotemporal in situ hybridization of all 49 zebrafish hox genes in wild-type vs. Cdx4-deficient embryos\",\n      \"pmids\": [\"26335559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CDX4 differentially times distinct paralog groups is unknown\", \"Single lab, awaits independent confirmation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reciprocal inhibition between CDX4 and retinoic acid/Cyp26a1 was shown to position the hindbrain–spinal cord boundary: CDX4 suppresses Cyp26a1 posteriorly while RA inhibits cdx4 rostrally.\",\n      \"evidence\": \"Chemical RA inhibitors, morpholino knockdown, in situ hybridization for boundary markers in zebrafish\",\n      \"pmids\": [\"26773000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDX4 directly represses cyp26a1 transcription or acts indirectly is unresolved\", \"Single lab, morpholino-based\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"In human PSC differentiation, CDX4 was shown to be expressed exclusively in definitive hematopoietic mesoderm and to be both necessary and sufficient to specify definitive over primitive hematopoiesis, translating zebrafish findings to the human system.\",\n      \"evidence\": \"Stage-specific hPSC differentiation, CDX4 overexpression and knockout hPSCs, flow cytometry with CD235a/KDR lineage markers\",\n      \"pmids\": [\"28408465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional program in human definitive progenitors not fully mapped\", \"Whether CDX4 is sufficient for engraftable definitive HSCs not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two new functional domains of CDX4 were defined: it drives transplantable acute erythroid leukemia via stemness gene upregulation and GATA1/2 suppression, and it acts as a dual-function regulator in spinal cord neural progenitors by simultaneously repressing Nkx1.2 and activating Pax6 while preventing premature neuronal differentiation.\",\n      \"evidence\": \"Retroviral Cdx4 overexpression in mouse bone marrow transplant model with transcriptomic/proteomic profiling; chicken pre-neural tube gain- and loss-of-function with marker analysis\",\n      \"pmids\": [\"31770439\", \"30825428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect regulation of GATA1/2 by CDX4 not distinguished\", \"Neural progenitor targets identified only in chicken; mammalian conservation not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CDX4 was found to function cell-autonomously in trunk neural crest cells, directly binding NC-specific enhancers to regulate foxd3 and control segmental NC migration, expanding CDX4's role beyond mesoderm and endoderm patterning.\",\n      \"evidence\": \"ChIP for enhancer binding, mutant analysis, cell transplantation chimera experiments in zebrafish\",\n      \"pmids\": [\"34389276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of CDX4-bound NC enhancers not catalogued genome-wide\", \"Whether CDX4 regulates NC in amniotes not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of CDX4–menin and CDX4–cofactor interactions, whether CDX4 mutations directly cause human Mendelian disease or contribute to human AML, and how CDX4's dual activating/repressing functions are mechanistically switched at different genomic targets.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of CDX4 or its complexes\", \"No human genetic disease directly attributed to CDX4 mutations\", \"Genome-wide binding data in mammalian hematopoietic or neural progenitors lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 5, 9, 12, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 6, 9, 12, 14, 17, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5, 9, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [2, 10, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 4, 6, 14, 15, 17, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 7, 9, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"menin\", \"SALL4\", \"HOXA10\", \"HOXA9\", \"LEF1\", \"CTNNB1\", \"TCF3\", \"CDX2\"],\n    \"other_free_text\": []\n  }\n}\n```"}