Allelic expression imbalance of CDKN2A variants in childhood acute lymphoblastic leukemia.
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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 16Ink4a-defective Ba/F3 cell model overexpressing functional p16INK4A variants showed enhanced susceptibility to transformation by BCR-ABL1-, NRASG12D-, and JAK2R683G + CRLF2-. Notably, the variant p16INK4A exhibited higher transcription level than wild-type allele in co-expression studies. While CDK4/6 inhibitor partially suppressed NRASG12D-, and JAK2R683G + 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 p16INK4A expression. CONCLUSION: These findings illuminate how inherited CDKN2A genetic variations of coding region influence ALL development through AEI mechanisms.