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 : 2025-03-04 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

{"title":"Allelic expression imbalance of CDKN2A variants in childhood acute lymphoblastic leukemia.","authors":"Zhexuan Tang, Kunlin Pei, Haoyu Xu, Yongzhi Zheng, Shuquan Zhuang, Kaizhi Weng, Yingyi He, Jing Wu, Hui Zhang","doi":"10.1007/s13402-025-01049-6","DOIUrl":null,"url":null,"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 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.","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13402-025-01049-6","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

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.

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

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.