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Allelic expression imbalance of CDKN2A variants in childhood acute lymphoblastic leukemia.

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Název: Allelic expression imbalance of CDKN2A variants in childhood acute lymphoblastic leukemia.
Autoři: Tang, Zhexuan, Pei, Kunlin, Xu, Haoyu, Zheng, Yongzhi, Zhuang, Shuquan, Weng, Kaizhi, He, Yingyi, Wu, Jing, Zhang, Hui
Zdroj: Cellular Oncology (2211-3428); Jun2025, Vol. 48 Issue 3, p835-839, 5p
Témata: GENE expression, LYMPHOBLASTIC leukemia, GENETIC variation, CYCLIN-dependent kinase inhibitors, ACUTE leukemia
Abstrakt: 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. [ABSTRACT FROM AUTHOR]
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Databáze: Complementary Index
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Abstrakt: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<sup>Ink4a</sup>-defective Ba/F3 cell model overexpressing functional p16<sup>INK4A</sup> variants showed enhanced susceptibility to transformation by BCR–ABL1-, NRAS<sup>G12D</sup>-, and JAK2<sup>R683G</sup> + CRLF2-. Notably, the variant p16<sup>INK4A</sup> exhibited higher transcription level than wild-type allele in co-expression studies. While CDK4/6 inhibitor partially suppressed NRAS<sup>G12D</sup>-, and JAK2<sup>R683G</sup> + 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<sup>INK4A</sup> expression. Conclusion: These findings illuminate how inherited CDKN2A genetic variations of coding region influence ALL development through AEI mechanisms. [ABSTRACT FROM AUTHOR]
ISSN:22113428
DOI:10.1007/s13402-025-01049-6