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

IF 4.9 2区医学 Q2 CELL BIOLOGY

Cellular Oncology Pub Date : 2025-06-01 Epub Date: 2025-03-04 DOI:10.1007/s13402-025-01049-6

Zhexuan Tang, Kunlin Pei, Haoyu Xu, Yongzhi Zheng, Shuquan Zhuang, Kaizhi Weng, Yingyi He, Jing Wu, Hui Zhang

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引用次数: 0

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.

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CDKN2A变异在儿童急性淋巴细胞白血病中的等位基因表达失衡。

生殖系CDKN2A变异通过等位基因表达不平衡（AEI）易患儿童急性淋巴细胞白血病（ALL）。因此，尚不清楚这些种系变异是如何起作用的，以及它们是否都通过AEI赋予B-ALL易感性。方法和结果：使用等位基因特异性Taqman PCR检测，我们证明与造血细胞相比，白血病细胞优先表达这些功能遗传编码变体。在固有的p16INK4A缺陷的Ba/F3细胞模型中，过表达功能p16INK4A变异体对BCR-ABL1-、NRASG12D-和JAK2R683G + CRLF2-的转化易感性增强。值得注意的是，在共表达研究中，变异p16INK4A比野生型等位基因表现出更高的转录水平。虽然CDK4/6抑制剂部分抑制NRASG12D-和JAK2R683G + crlf2诱导的白血病转化，但对bcr - abl1诱导的白血病转化无效。差异基因表达分析显示m6a相关基因PRRC2A上调，其敲除部分恢复了野生型p16INK4A的表达。结论：这些发现阐明了CDKN2A编码区的遗传变异如何通过AEI机制影响ALL的发展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular Oncology ONCOLOGY-CELL BIOLOGY

CiteScore

10.30

自引率

1.50%

发文量

审稿时长

12 months

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.