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Introduction <p>Germline <i>CDKN2A</i> 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. </p> Methods and results <p>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 <i>p</i> 16<sup>Ink4a</sup>-defective Ba/F3 cell model overexpressing functional <i>p16</i><sup><i>INK4A</i></sup> variants showed enhanced susceptibility to transformation by <i>BCR</i>–<i>ABL1-</i>, <i>NRAS</i><sup><i>G12D</i></sup><i>-</i>, and <i>JAK2</i><sup><i>R683G</i></sup> + <i>CRLF2</i>-. Notably, the variant <i>p16</i><sup><i>INK4A</i></sup> exhibited higher transcription level than wild-type allele in co-expression studies. While CDK4/6 inhibitor partially suppressed <i>NRAS</i><sup><i>G12D</i></sup>-, and <i>JAK2</i><sup><i>R683G</i></sup> + <i>CRLF2</i>-induced transformation, it proved ineffective against <i>BCR</i>-<i>ABL1</i>-induced leukemic transformation. Differential gene expression analysis revealed upregulation of m6A-related gene <i>PRRC2A</i>, whose knockout partially restored wild-type <i>p16</i><sup><i>INK4A</i></sup> expression. </p> Conclusion <p>These findings illuminate how inherited <i>CDKN2A</i> genetic variations of coding region influence ALL development through AEI mechanisms.</p>

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Allelic expression imbalance of CDKN2A variants in childhood acute lymphoblastic leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月4日

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

摘要

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.