Hematology (Amsterdam, Netherlands) · 2026
OVCA2 acts as an oncogene in pediatric AML by negatively regulating CDKN1A to drive cell cycle progression.
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Jiao Wanyan, Cheng Saisai, Yang Xiao, Liu Haiyan, Tang Xiaodong, Li Qianlong, Li Ying, Zhou Bi
Аннотация
OBJECTIVES: Pediatric acute myeloid leukemia (AML) is biologically distinct from adult AML and carries a poor prognosis. OVCA2, a serine hydrolase with context-dependent roles, has unknown function in AML. We aimed to investigate its role, regulation, and clinical significance in pediatric AML.
METHODS: OVCA2 was identified as a downstream target of a pediatric AML-specific core transcriptional regulatory circuit using CUT&Tag integrative analysis. Expression and prognostic associations were assessed in TARGET (pediatric) and TCGA (adult) datasets. Functional validation via lentiviral shRNA knockdown was performed in MV4-11 and Kasumi-1 cells using CCK-8, colony formation, and cell cycle assays. RNA-seq and GSEA elucidated mechanisms. Co-knockdown of CDKN1A tested functional rescue.
RESULTS: OVCA2 was significantly upregulated in AML and correlated with worse overall survival exclusively in the pediatric cohort. Knockdown impaired proliferation, colony formation, and induced G1 arrest, with reduced C-MYC and CDK2 levels. Transcriptomic analysis revealed activation of 'Negative Regulation of Cell Population Proliferation' pathway, with CDKN1A as a top upregulated gene. Co-knockdown of CDKN1A partially rescued the anti-proliferative effect.
DISCUSSION: OVCA2 acts as a novel oncogene in pediatric AML by transcriptionally repressing CDKN1A to drive cell cycle progression. Its age-specific prognostic association and origin from a pediatric AML core regulatory circuit highlight its role in age-related regulatory networks.
CONCLUSION: OVCA2 represents a promising therapeutic target in pediatric AML, with its effects mediated through CDKN1A repression.
METHODS: OVCA2 was identified as a downstream target of a pediatric AML-specific core transcriptional regulatory circuit using CUT&Tag integrative analysis. Expression and prognostic associations were assessed in TARGET (pediatric) and TCGA (adult) datasets. Functional validation via lentiviral shRNA knockdown was performed in MV4-11 and Kasumi-1 cells using CCK-8, colony formation, and cell cycle assays. RNA-seq and GSEA elucidated mechanisms. Co-knockdown of CDKN1A tested functional rescue.
RESULTS: OVCA2 was significantly upregulated in AML and correlated with worse overall survival exclusively in the pediatric cohort. Knockdown impaired proliferation, colony formation, and induced G1 arrest, with reduced C-MYC and CDK2 levels. Transcriptomic analysis revealed activation of 'Negative Regulation of Cell Population Proliferation' pathway, with CDKN1A as a top upregulated gene. Co-knockdown of CDKN1A partially rescued the anti-proliferative effect.
DISCUSSION: OVCA2 acts as a novel oncogene in pediatric AML by transcriptionally repressing CDKN1A to drive cell cycle progression. Its age-specific prognostic association and origin from a pediatric AML core regulatory circuit highlight its role in age-related regulatory networks.
CONCLUSION: OVCA2 represents a promising therapeutic target in pediatric AML, with its effects mediated through CDKN1A repression.