Allelic expression imbalance of CDKN2A variants in childhood acute lymphoblastic leukemia

Cell Oncol (Dordr). 2025 Mar 4. doi: 10.1007/s13402-025-01049-6. Online ahead of print.

ABSTRACT

INTRODUCTION: Germline CDKN2A variant predisposes to childhood acute lymphoblastic leukemia (ALL) through allelic expression imbalance (AEI). It is unknown, therefore, how these germline variations work and whether they all confer B-ALL susceptibility through AEI.

METHODS AND RESULTS: Using allele-specific Taqman PCR assays, we demonstrated that preferentially expressed of those functional inherited coding variants in leukemic cells compared to hematopoietic cells. In an inherent p 16^Ink4a-defective Ba/F3 cell model overexpressing functional p16^INK4A variants showed enhanced susceptibility to transformation by BCR-ABL1-, NRAS^G12D-, and JAK2^R683G + CRLF2-. Notably, the variant p16^INK4A exhibited higher transcription level than wild-type allele in co-expression studies. While CDK4/6 inhibitor partially suppressed NRAS^G12D-, and JAK2^R683G + CRLF2-induced transformation, it proved ineffective against BCR-ABL1-induced leukemic transformation. Differential gene expression analysis revealed upregulation of m6A-related gene PRRC2A, whose knockout partially restored wild-type p16^INK4A expression.

CONCLUSION: These findings illuminate how inherited CDKN2A genetic variations of coding region influence ALL development through AEI mechanisms.

PMID:40035982 | DOI:10.1007/s13402-025-01049-6