OVCA2 acts as an oncogene in pediatric AML by negatively regulating CDKN1A to drive cell cycle progression

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.

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.

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.

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.

OVCA2 represents a promising therapeutic target in pediatric AML, with its effects mediated through CDKN1A repression.