Frontiers in immunology · 2025
HOXA5-mediated spatial remodeling of tumor-immune interfaces across cancers promotes AML pathogenesis.
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Zhang Changling, Wen Ping, Zeng Yan, Chen Tao, Guo Qulian, Liu Chunyan, Zhong Fangfang
Аннотация
BACKGROUND: HOXA5 (homeobox A5) exhibits context-dependent roles in cancer, but its pan-cancer spatial immune regulatory functions and therapeutic potential remain poorly understood.
METHODS: We integrated multi-omics data from 33 cancer types (TCGA, n=11,096; GTEx, n=7,469; TISCH2; spatial transcriptomics) to characterize HOXA5 expression, genomic alterations, and immune interactions. Functional validation was performed in AML cell lines (U937, KG-1; n=3 biological replicates per experiment).
RESULTS: HOXA5 was significantly dysregulated across cancers, with elevated expression in AML and GBM, and reduced expression in BRCA and LUAD. In AML, high HOXA5 expression predicted poor overall survival (HR = 2.80, 95% CI: 1.60-4.89, p < 0.001) and was associated with FLT3/NPM1 mutations. Spatial transcriptomics revealed HOXA5+ malignant cells enhance fibroblast/endothelial crosstalk via IGFBP3-TMEM219. HOXA5 knockdown suppressed proliferation (p < 0.01) and induced G0/G1 arrest. Mechanistically, HOXA5 maintained AML through cholesterol biosynthesis and ECM remodeling. Mercaptopurine was identified as a potential therapeutic agent, and molecular docking predicted a potential stable interaction with HOXA5.
CONCLUSIONS: HOXA5 plays a dual role in solid versus hematologic malignancies and serves as a key spatial immune regulator. It is a robust prognostic biomarker and therapeutic target in AML, with mercaptopurine representing a promising repurposing candidate.
METHODS: We integrated multi-omics data from 33 cancer types (TCGA, n=11,096; GTEx, n=7,469; TISCH2; spatial transcriptomics) to characterize HOXA5 expression, genomic alterations, and immune interactions. Functional validation was performed in AML cell lines (U937, KG-1; n=3 biological replicates per experiment).
RESULTS: HOXA5 was significantly dysregulated across cancers, with elevated expression in AML and GBM, and reduced expression in BRCA and LUAD. In AML, high HOXA5 expression predicted poor overall survival (HR = 2.80, 95% CI: 1.60-4.89, p < 0.001) and was associated with FLT3/NPM1 mutations. Spatial transcriptomics revealed HOXA5+ malignant cells enhance fibroblast/endothelial crosstalk via IGFBP3-TMEM219. HOXA5 knockdown suppressed proliferation (p < 0.01) and induced G0/G1 arrest. Mechanistically, HOXA5 maintained AML through cholesterol biosynthesis and ECM remodeling. Mercaptopurine was identified as a potential therapeutic agent, and molecular docking predicted a potential stable interaction with HOXA5.
CONCLUSIONS: HOXA5 plays a dual role in solid versus hematologic malignancies and serves as a key spatial immune regulator. It is a robust prognostic biomarker and therapeutic target in AML, with mercaptopurine representing a promising repurposing candidate.