{"gene":"MXRA7","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2022,"finding":"MXRA7 protein localizes to the cytoplasm of SHI-1 leukemia cells, and overexpression of MXRA7 inhibits drug-induced apoptosis by upregulating BCL-2 protein expression.","method":"Laser confocal microscopy for localization; Western blot for BCL-2; Annexin V/7-AAD staining for apoptosis in stable lentiviral overexpression cell line","journal":"Zhongguo shi yan xue ye xue za zhi","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, multiple orthogonal methods (confocal, Western blot, flow cytometry) but no reconstitution or mutagenesis","pmids":["35680791"],"is_preprint":false},{"year":2023,"finding":"MXRA7 knockdown in NB4 acute promyelocytic leukemia cells promotes ATRA-induced differentiation by decreasing PML-RARα protein levels and increasing PML and RARα levels; knockdown also upregulates C/EBPβ, C/EBPδ, and UBE2L6 and downregulates KDM5A, CCND2, and SPARC.","method":"shRNA knockdown, Western blot for PML-RARα/PML/RARα, gene expression analysis, xenograft NOD-SCID mouse model","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple molecular readouts, in vivo validation, single lab","pmids":["37419299"],"is_preprint":false},{"year":2023,"finding":"MXRA7 knockdown in REH B-ALL cells inhibits proliferation, arrests cells in G0/G1, and increases sensitivity to cytarabine-induced apoptosis via activation of caspase-3 and caspase-9.","method":"shRNA knockdown, CCK-8 proliferation assay, PI staining for cell cycle, Annexin V/7-AAD apoptosis assay, Western blot for caspase-3/-9","journal":"Zhongguo shi yan xue ye xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single paper, multiple assays but no pathway reconstitution or mechanistic follow-up beyond caspase detection","pmids":["36765476"],"is_preprint":false},{"year":2023,"finding":"MXRA7 knockout in mice reduces megakaryocyte numbers in bone marrow and spleen, decreases peripheral platelet counts, and impairs platelet function; mechanistically, MXRA7 loss suppresses GATA-1 and FOG-1 expression and inhibits ERK/MAPK signaling and β-tubulin expression, blocking proplatelet formation.","method":"MXRA7 knockout mice, bone marrow/spleen histology, platelet function assays, Western blot for GATA-1/FOG-1/ERK/β-tubulin, knockdown in MEG-01 cells","journal":"Blood science (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse model with defined phenotype, multiple molecular readouts, single lab","pmids":["37546710"],"is_preprint":false},{"year":2024,"finding":"MXRA7 knockdown in THP-1 monocytic cells promotes monocyte-to-macrophage differentiation and biases differentiation toward M1 macrophages (elevated TNF-α, IL-1β, IL-6) by upregulating adhesion molecules VCAM-1 and ICAM-1 and activating NF-κB p52/p100 and MAPK signaling pathways.","method":"shRNA knockdown in THP-1 cells, flow cytometry, ELISA for cytokines, Western blot for NF-κB/MAPK components, RNA sequencing, adhesion assays","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined differentiation phenotype, RNA-seq plus Western blot, single lab, multiple orthogonal methods","pmids":["38735126"],"is_preprint":false},{"year":2018,"finding":"MXRA7-deficient mice develop more severe imiquimod-induced psoriasis-like disease than wild-type mice, with higher levels of pro-psoriatic cytokines (IL-17, IL-22, IL-23) and increased keratinocyte proliferation upon differentiation induction, indicating MXRA7 functions as a negative modulator of psoriasis development.","method":"MXRA7 knockout mice, imiquimod psoriasis model, immunohistochemistry, RT-PCR for cytokines, keratinocyte proliferation assay in culture","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse disease model with defined phenotype and molecular readouts, single lab","pmids":["29781547"],"is_preprint":false},{"year":2026,"finding":"MXRA7 deficiency in aged mice markedly increases Macro1 macrophages in bone marrow, likely through dysregulation of the Ccl24-Ccr3 signaling axis; MXRA7 loss also alters Mid1 expression and macrophage migration inhibitory factor signaling pairs (Cd74+Cxcr4, Ccl6+Ccr2, and Itga2b+Itgb3), coordinating hematopoietic and immune homeostasis during aging.","method":"Single-cell RNA sequencing on bone marrow from young and aged wild-type vs. MXRA7-knockout mice; ligand-receptor interaction analysis","journal":"Blood science (Baltimore, Md.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, scRNA-seq is correlative; pathway assignments inferred from sequencing data without functional validation experiments","pmids":["42220555"],"is_preprint":false},{"year":2011,"finding":"PS1TP1 (alias MXRA7) protein acts as a transcriptional activator; suppression subtractive hybridization of HepG2 cells transfected with pcDNA3.1-PS1TP1 identified 12 putative downstream target genes involved in cell cycle regulation, metabolism, immunity, and apoptosis.","method":"Suppression subtractive hybridization (SSH) of PS1TP1-transfected HepG2 cells vs. empty vector controls; nested PCR, cloning, sequencing, and bioinformatics","journal":"Zhonghua shi yan he lin chuang bing du xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — SSH is a discovery/screening technique; no functional validation of individual targets; single lab, no replication","pmids":["21977585"],"is_preprint":false}],"current_model":"MXRA7 is a cytoplasmic matrix-remodeling-associated protein that functions as a negative regulator of cellular differentiation and immune activation: it suppresses monocyte-to-macrophage differentiation via NF-κB/MAPK pathways, blocks ATRA-induced differentiation in acute promyelocytic leukemia cells by stabilizing PML-RARα, supports megakaryocyte differentiation and platelet production through ERK/MAPK signaling and GATA-1/FOG-1 expression, modulates drug-induced apoptosis via BCL-2 upregulation, and restrains psoriatic keratinocyte proliferation, with additional roles in bone marrow aging through macrophage polarization and Ccl24-Ccr3 axis regulation."},"narrative":{"mechanistic_narrative":"MXRA7 is a cytoplasmic protein that acts as a broad negative regulator of hematopoietic and immune cell differentiation while supporting survival programs in leukemic and normal cells [PMID:35680791, PMID:38735126]. In leukemia models it promotes cell survival: overexpression in SHI-1 cells blunts drug-induced apoptosis through upregulation of BCL-2 [PMID:35680791], and its knockdown in NB4 acute promyelocytic leukemia cells lowers PML-RARα while restoring PML and RARα to potentiate ATRA-induced differentiation [PMID:37419299]. As a brake on myeloid maturation, MXRA7 knockdown in THP-1 monocytes accelerates monocyte-to-macrophage differentiation and skews toward an inflammatory M1 state with elevated TNF-α, IL-1β, and IL-6, coupled to induction of VCAM-1 and ICAM-1 and activation of NF-κB (p52/p100) and MAPK signaling [PMID:38735126]. In the megakaryocyte lineage MXRA7 conversely supports differentiation, as its loss in mice reduces megakaryocyte numbers, platelet counts, and proplatelet formation through diminished GATA-1/FOG-1 expression and ERK/MAPK signaling [PMID:37546710]. Consistent with an anti-inflammatory role in tissue, MXRA7-deficient mice develop exacerbated imiquimod-induced psoriasis with heightened IL-17/IL-22/IL-23 and keratinocyte proliferation [PMID:29781547]. Beyond these lineage and inflammatory phenotypes, no direct biochemical activity or binding partner for MXRA7 has been defined in the available corpus.","teleology":[{"year":2011,"claim":"An initial functional handle suggested MXRA7 (as alias PS1TP1) could influence gene expression, framing it as a regulator with downstream transcriptional consequences.","evidence":"Suppression subtractive hybridization of PS1TP1-transfected HepG2 cells identifying putative downstream targets","pmids":["21977585"],"confidence":"Low","gaps":["SSH is a screening method with no functional validation of individual targets","No demonstration of direct DNA binding or transcriptional activity","Single lab, no replication"]},{"year":2018,"claim":"The first in vivo loss-of-function model established MXRA7 as a negative modulator of inflammatory tissue pathology, moving it from screen candidate to physiological regulator.","evidence":"MXRA7 knockout mice in an imiquimod psoriasis model with cytokine RT-PCR and keratinocyte proliferation assays","pmids":["29781547"],"confidence":"Medium","gaps":["Cell type responsible for the phenotype not resolved (keratinocyte-intrinsic vs immune)","No molecular mechanism linking MXRA7 to IL-17/IL-22/IL-23 induction","No biochemical activity defined"]},{"year":2022,"claim":"MXRA7 was tied to a survival program in leukemia, explaining how it could restrain apoptosis.","evidence":"Confocal localization plus Western blot for BCL-2 and Annexin V/7-AAD apoptosis assays in stable MXRA7-overexpressing SHI-1 cells","pmids":["35680791"],"confidence":"Medium","gaps":["Mechanism connecting MXRA7 to BCL-2 expression unknown","No rescue or mutagenesis to establish causality","Single cell line"]},{"year":2023,"claim":"Knockdown studies positioned MXRA7 as a brake on differentiation and a stabilizer of the PML-RARα oncoprotein, linking it to ATRA responsiveness in APL.","evidence":"shRNA knockdown in NB4 cells with Western blots for PML-RARα/PML/RARα plus expression profiling and a NOD-SCID xenograft","pmids":["37419299"],"confidence":"Medium","gaps":["Whether MXRA7 physically interacts with or directly stabilizes PML-RARα is unknown","Mechanism of the accompanying transcriptional changes (C/EBPβ/δ, KDM5A, etc.) not defined"]},{"year":2023,"claim":"Parallel work in B-ALL extended the pro-proliferative/anti-apoptotic role of MXRA7 to another leukemia context.","evidence":"shRNA knockdown in REH cells with proliferation, cell-cycle, apoptosis assays and caspase-3/-9 Western blots","pmids":["36765476"],"confidence":"Low","gaps":["No pathway reconstitution beyond caspase detection","Single paper, single lab","Upstream mechanism for cell-cycle arrest unknown"]},{"year":2023,"claim":"A knockout mouse revealed a lineage-specific positive role, showing MXRA7 is required for megakaryopoiesis and platelet production via GATA-1/FOG-1 and ERK/MAPK signaling.","evidence":"MXRA7 knockout mice with bone marrow/spleen histology, platelet assays, GATA-1/FOG-1/ERK/β-tubulin Western blots, and MEG-01 knockdown","pmids":["37546710"],"confidence":"Medium","gaps":["How MXRA7 connects to GATA-1/FOG-1 expression mechanistically is unknown","Direct molecular partners in megakaryocytes unidentified"]},{"year":2024,"claim":"RNA-seq plus pathway dissection clarified that MXRA7 suppresses monocyte-to-macrophage differentiation and M1 polarization through adhesion molecules and NF-κB/MAPK signaling.","evidence":"shRNA knockdown in THP-1 cells with flow cytometry, cytokine ELISA, RNA sequencing, adhesion assays, and Western blots for NF-κB/MAPK","pmids":["38735126"],"confidence":"Medium","gaps":["Direct molecular target of MXRA7 upstream of NF-κB/MAPK not identified","No demonstration of direct binding to any signaling component"]},{"year":2026,"claim":"Single-cell profiling extended MXRA7 function to bone marrow aging, implicating it in macrophage population dynamics and chemokine signaling.","evidence":"scRNA-seq of young/aged wild-type vs MXRA7-knockout bone marrow with ligand-receptor interaction analysis","pmids":["42220555"],"confidence":"Low","gaps":["scRNA-seq associations are correlative without functional validation","Ccl24-Ccr3 axis link inferred, not experimentally tested","Mechanism by which MXRA7 alters macrophage populations unknown"]},{"year":null,"claim":"The fundamental biochemical activity of MXRA7 remains undefined: no enzymatic function, direct binding partner, or structural mechanism has been established to explain its consistent regulatory effects across lineages.","evidence":"No direct biochemical or interaction data in the available corpus","pmids":[],"confidence":"Low","gaps":["No defined molecular activity","No validated direct physical partner","No structural model linking MXRA7 to NF-κB/MAPK/ERK or PML-RARα"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,3,4]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P84157","full_name":"Matrix-remodeling-associated protein 7","aliases":[],"length_aa":204,"mass_kda":21.5,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P84157/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MXRA7","classification":"Common Essential","n_dependent_lines":435,"n_total_lines":1208,"dependency_fraction":0.36009933774834435},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MAP2K1","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MXRA7","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MXRA7"},"hgnc":{"alias_symbol":["FLJ46603","TMAP1","PS1TP1"],"prev_symbol":[]},"alphafold":{"accession":"P84157","domains":[{"cath_id":"1.10.287","chopping":"150-204","consensus_level":"medium","plddt":84.2385,"start":150,"end":204}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P84157","model_url":"https://alphafold.ebi.ac.uk/files/AF-P84157-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P84157-F1-predicted_aligned_error_v6.png","plddt_mean":64.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MXRA7","jax_strain_url":"https://www.jax.org/strain/search?query=MXRA7"},"sequence":{"accession":"P84157","fasta_url":"https://rest.uniprot.org/uniprotkb/P84157.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P84157/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P84157"}},"corpus_meta":[{"pmid":"28847716","id":"PMC_28847716","title":"Public data mining plus domestic experimental study defined involvement of the old-yet-uncharacterized gene matrix-remodeling associated 7 (MXRA7) in physiopathology of the eye.","date":"2017","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/28847716","citation_count":16,"is_preprint":false},{"pmid":"29781547","id":"PMC_29781547","title":"Altered expression of matrix remodelling associated 7 (MXRA7) in psoriatic epidermis: Evidence for a protective role in the psoriasis imiquimod mouse model.","date":"2018","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29781547","citation_count":14,"is_preprint":false},{"pmid":"37419299","id":"PMC_37419299","title":"Critical role of MXRA7 in differentiation blockade in human acute promyelocytic leukemia cells.","date":"2023","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/37419299","citation_count":5,"is_preprint":false},{"pmid":"38735126","id":"PMC_38735126","title":"MXRA7 is involved in monocyte-to-macrophage differentiation.","date":"2024","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38735126","citation_count":4,"is_preprint":false},{"pmid":"37546710","id":"PMC_37546710","title":"MXRA7 is involved in megakaryocyte differentiation and platelet production.","date":"2023","source":"Blood science (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/37546710","citation_count":3,"is_preprint":false},{"pmid":"35680791","id":"PMC_35680791","title":"[The Effect of Matrix Remodeling Associated 7 (MXRA7) Expression on the Biological Function of SHI-1 Cells].","date":"2022","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/35680791","citation_count":3,"is_preprint":false},{"pmid":"36765476","id":"PMC_36765476","title":"[Effect of MXRA7 on the Biological Functions of Acute B Lymphoblastic Leukemia Cell Line REH].","date":"2023","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/36765476","citation_count":2,"is_preprint":false},{"pmid":"40459788","id":"PMC_40459788","title":"Bibliometric analysis of MXRA7 gene research trajectory: trends and insights (2015-2024).","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40459788","citation_count":0,"is_preprint":false},{"pmid":"21977585","id":"PMC_21977585","title":"[Screening of the target genes transactivated by PS1TP1 protein with suppression subtractive hybridization technique].","date":"2011","source":"Zhonghua shi yan he lin chuang bing du xue za zhi = Zhonghua shiyan he linchuang bingduxue zazhi = Chinese journal of experimental and clinical virology","url":"https://pubmed.ncbi.nlm.nih.gov/21977585","citation_count":0,"is_preprint":false},{"pmid":"42220555","id":"PMC_42220555","title":"The role of MXRA7 in bone marrow senescence involves macrophage polarization and microenvironment remodeling.","date":"2026","source":"Blood science (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/42220555","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.01.25324976","title":"A framework for studying multi-omic risk factors and their interplay: application to coronary artery disease","date":"2025-04-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.01.25324976","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.04.24316062","title":"A 5-transcript signature for discriminating viral and bacterial etiology in pediatric pneumonia","date":"2024-11-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.04.24316062","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8134,"output_tokens":2183,"usd":0.028574,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9203,"output_tokens":2984,"usd":0.060307,"stage2_stop_reason":"end_turn"},"total_usd":0.088881,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"MXRA7 protein localizes to the cytoplasm of SHI-1 leukemia cells, and overexpression of MXRA7 inhibits drug-induced apoptosis by upregulating BCL-2 protein expression.\",\n      \"method\": \"Laser confocal microscopy for localization; Western blot for BCL-2; Annexin V/7-AAD staining for apoptosis in stable lentiviral overexpression cell line\",\n      \"journal\": \"Zhongguo shi yan xue ye xue za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, multiple orthogonal methods (confocal, Western blot, flow cytometry) but no reconstitution or mutagenesis\",\n      \"pmids\": [\"35680791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MXRA7 knockdown in NB4 acute promyelocytic leukemia cells promotes ATRA-induced differentiation by decreasing PML-RARα protein levels and increasing PML and RARα levels; knockdown also upregulates C/EBPβ, C/EBPδ, and UBE2L6 and downregulates KDM5A, CCND2, and SPARC.\",\n      \"method\": \"shRNA knockdown, Western blot for PML-RARα/PML/RARα, gene expression analysis, xenograft NOD-SCID mouse model\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple molecular readouts, in vivo validation, single lab\",\n      \"pmids\": [\"37419299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MXRA7 knockdown in REH B-ALL cells inhibits proliferation, arrests cells in G0/G1, and increases sensitivity to cytarabine-induced apoptosis via activation of caspase-3 and caspase-9.\",\n      \"method\": \"shRNA knockdown, CCK-8 proliferation assay, PI staining for cell cycle, Annexin V/7-AAD apoptosis assay, Western blot for caspase-3/-9\",\n      \"journal\": \"Zhongguo shi yan xue ye xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single paper, multiple assays but no pathway reconstitution or mechanistic follow-up beyond caspase detection\",\n      \"pmids\": [\"36765476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MXRA7 knockout in mice reduces megakaryocyte numbers in bone marrow and spleen, decreases peripheral platelet counts, and impairs platelet function; mechanistically, MXRA7 loss suppresses GATA-1 and FOG-1 expression and inhibits ERK/MAPK signaling and β-tubulin expression, blocking proplatelet formation.\",\n      \"method\": \"MXRA7 knockout mice, bone marrow/spleen histology, platelet function assays, Western blot for GATA-1/FOG-1/ERK/β-tubulin, knockdown in MEG-01 cells\",\n      \"journal\": \"Blood science (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse model with defined phenotype, multiple molecular readouts, single lab\",\n      \"pmids\": [\"37546710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MXRA7 knockdown in THP-1 monocytic cells promotes monocyte-to-macrophage differentiation and biases differentiation toward M1 macrophages (elevated TNF-α, IL-1β, IL-6) by upregulating adhesion molecules VCAM-1 and ICAM-1 and activating NF-κB p52/p100 and MAPK signaling pathways.\",\n      \"method\": \"shRNA knockdown in THP-1 cells, flow cytometry, ELISA for cytokines, Western blot for NF-κB/MAPK components, RNA sequencing, adhesion assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined differentiation phenotype, RNA-seq plus Western blot, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38735126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MXRA7-deficient mice develop more severe imiquimod-induced psoriasis-like disease than wild-type mice, with higher levels of pro-psoriatic cytokines (IL-17, IL-22, IL-23) and increased keratinocyte proliferation upon differentiation induction, indicating MXRA7 functions as a negative modulator of psoriasis development.\",\n      \"method\": \"MXRA7 knockout mice, imiquimod psoriasis model, immunohistochemistry, RT-PCR for cytokines, keratinocyte proliferation assay in culture\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse disease model with defined phenotype and molecular readouts, single lab\",\n      \"pmids\": [\"29781547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MXRA7 deficiency in aged mice markedly increases Macro1 macrophages in bone marrow, likely through dysregulation of the Ccl24-Ccr3 signaling axis; MXRA7 loss also alters Mid1 expression and macrophage migration inhibitory factor signaling pairs (Cd74+Cxcr4, Ccl6+Ccr2, and Itga2b+Itgb3), coordinating hematopoietic and immune homeostasis during aging.\",\n      \"method\": \"Single-cell RNA sequencing on bone marrow from young and aged wild-type vs. MXRA7-knockout mice; ligand-receptor interaction analysis\",\n      \"journal\": \"Blood science (Baltimore, Md.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, scRNA-seq is correlative; pathway assignments inferred from sequencing data without functional validation experiments\",\n      \"pmids\": [\"42220555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PS1TP1 (alias MXRA7) protein acts as a transcriptional activator; suppression subtractive hybridization of HepG2 cells transfected with pcDNA3.1-PS1TP1 identified 12 putative downstream target genes involved in cell cycle regulation, metabolism, immunity, and apoptosis.\",\n      \"method\": \"Suppression subtractive hybridization (SSH) of PS1TP1-transfected HepG2 cells vs. empty vector controls; nested PCR, cloning, sequencing, and bioinformatics\",\n      \"journal\": \"Zhonghua shi yan he lin chuang bing du xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — SSH is a discovery/screening technique; no functional validation of individual targets; single lab, no replication\",\n      \"pmids\": [\"21977585\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MXRA7 is a cytoplasmic matrix-remodeling-associated protein that functions as a negative regulator of cellular differentiation and immune activation: it suppresses monocyte-to-macrophage differentiation via NF-κB/MAPK pathways, blocks ATRA-induced differentiation in acute promyelocytic leukemia cells by stabilizing PML-RARα, supports megakaryocyte differentiation and platelet production through ERK/MAPK signaling and GATA-1/FOG-1 expression, modulates drug-induced apoptosis via BCL-2 upregulation, and restrains psoriatic keratinocyte proliferation, with additional roles in bone marrow aging through macrophage polarization and Ccl24-Ccr3 axis regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MXRA7 is a cytoplasmic protein that acts as a broad negative regulator of hematopoietic and immune cell differentiation while supporting survival programs in leukemic and normal cells [#0, #4]. In leukemia models it promotes cell survival: overexpression in SHI-1 cells blunts drug-induced apoptosis through upregulation of BCL-2 [#0], and its knockdown in NB4 acute promyelocytic leukemia cells lowers PML-RARα while restoring PML and RARα to potentiate ATRA-induced differentiation [#1]. As a brake on myeloid maturation, MXRA7 knockdown in THP-1 monocytes accelerates monocyte-to-macrophage differentiation and skews toward an inflammatory M1 state with elevated TNF-α, IL-1β, and IL-6, coupled to induction of VCAM-1 and ICAM-1 and activation of NF-κB (p52/p100) and MAPK signaling [#4]. In the megakaryocyte lineage MXRA7 conversely supports differentiation, as its loss in mice reduces megakaryocyte numbers, platelet counts, and proplatelet formation through diminished GATA-1/FOG-1 expression and ERK/MAPK signaling [#3]. Consistent with an anti-inflammatory role in tissue, MXRA7-deficient mice develop exacerbated imiquimod-induced psoriasis with heightened IL-17/IL-22/IL-23 and keratinocyte proliferation [#5]. Beyond these lineage and inflammatory phenotypes, no direct biochemical activity or binding partner for MXRA7 has been defined in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"An initial functional handle suggested MXRA7 (as alias PS1TP1) could influence gene expression, framing it as a regulator with downstream transcriptional consequences.\",\n      \"evidence\": \"Suppression subtractive hybridization of PS1TP1-transfected HepG2 cells identifying putative downstream targets\",\n      \"pmids\": [\"21977585\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"SSH is a screening method with no functional validation of individual targets\",\n        \"No demonstration of direct DNA binding or transcriptional activity\",\n        \"Single lab, no replication\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The first in vivo loss-of-function model established MXRA7 as a negative modulator of inflammatory tissue pathology, moving it from screen candidate to physiological regulator.\",\n      \"evidence\": \"MXRA7 knockout mice in an imiquimod psoriasis model with cytokine RT-PCR and keratinocyte proliferation assays\",\n      \"pmids\": [\"29781547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cell type responsible for the phenotype not resolved (keratinocyte-intrinsic vs immune)\",\n        \"No molecular mechanism linking MXRA7 to IL-17/IL-22/IL-23 induction\",\n        \"No biochemical activity defined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"MXRA7 was tied to a survival program in leukemia, explaining how it could restrain apoptosis.\",\n      \"evidence\": \"Confocal localization plus Western blot for BCL-2 and Annexin V/7-AAD apoptosis assays in stable MXRA7-overexpressing SHI-1 cells\",\n      \"pmids\": [\"35680791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting MXRA7 to BCL-2 expression unknown\",\n        \"No rescue or mutagenesis to establish causality\",\n        \"Single cell line\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Knockdown studies positioned MXRA7 as a brake on differentiation and a stabilizer of the PML-RARα oncoprotein, linking it to ATRA responsiveness in APL.\",\n      \"evidence\": \"shRNA knockdown in NB4 cells with Western blots for PML-RARα/PML/RARα plus expression profiling and a NOD-SCID xenograft\",\n      \"pmids\": [\"37419299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MXRA7 physically interacts with or directly stabilizes PML-RARα is unknown\",\n        \"Mechanism of the accompanying transcriptional changes (C/EBPβ/δ, KDM5A, etc.) not defined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Parallel work in B-ALL extended the pro-proliferative/anti-apoptotic role of MXRA7 to another leukemia context.\",\n      \"evidence\": \"shRNA knockdown in REH cells with proliferation, cell-cycle, apoptosis assays and caspase-3/-9 Western blots\",\n      \"pmids\": [\"36765476\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No pathway reconstitution beyond caspase detection\",\n        \"Single paper, single lab\",\n        \"Upstream mechanism for cell-cycle arrest unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A knockout mouse revealed a lineage-specific positive role, showing MXRA7 is required for megakaryopoiesis and platelet production via GATA-1/FOG-1 and ERK/MAPK signaling.\",\n      \"evidence\": \"MXRA7 knockout mice with bone marrow/spleen histology, platelet assays, GATA-1/FOG-1/ERK/β-tubulin Western blots, and MEG-01 knockdown\",\n      \"pmids\": [\"37546710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How MXRA7 connects to GATA-1/FOG-1 expression mechanistically is unknown\",\n        \"Direct molecular partners in megakaryocytes unidentified\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"RNA-seq plus pathway dissection clarified that MXRA7 suppresses monocyte-to-macrophage differentiation and M1 polarization through adhesion molecules and NF-κB/MAPK signaling.\",\n      \"evidence\": \"shRNA knockdown in THP-1 cells with flow cytometry, cytokine ELISA, RNA sequencing, adhesion assays, and Western blots for NF-κB/MAPK\",\n      \"pmids\": [\"38735126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular target of MXRA7 upstream of NF-κB/MAPK not identified\",\n        \"No demonstration of direct binding to any signaling component\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Single-cell profiling extended MXRA7 function to bone marrow aging, implicating it in macrophage population dynamics and chemokine signaling.\",\n      \"evidence\": \"scRNA-seq of young/aged wild-type vs MXRA7-knockout bone marrow with ligand-receptor interaction analysis\",\n      \"pmids\": [\"42220555\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"scRNA-seq associations are correlative without functional validation\",\n        \"Ccl24-Ccr3 axis link inferred, not experimentally tested\",\n        \"Mechanism by which MXRA7 alters macrophage populations unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The fundamental biochemical activity of MXRA7 remains undefined: no enzymatic function, direct binding partner, or structural mechanism has been established to explain its consistent regulatory effects across lineages.\",\n      \"evidence\": \"No direct biochemical or interaction data in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No defined molecular activity\",\n        \"No validated direct physical partner\",\n        \"No structural model linking MXRA7 to NF-κB/MAPK/ERK or PML-RARα\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}