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<p>Aplastic anemia (AA) is a rare hematological disorder characterized by the failure of bone marrow hematopoiesis. Although somatic mutations are known to play pivotal roles in the pathogenesis and clinical progression of AA, their molecular characteristics in Chinese AA patients remain poorly characterized. In this study, we perform whole-exome sequencing on 126 Chinese AA patients to delineate the somatic mutation landscape. Our analysis reveal recurrently mutated genes enriched in immune regulatory pathways. Notably, we identify eight AA cases harboring mutations in the tyrosine kinase motif of C-terminal Src kinase (<i>CSK</i>), a critical regulator of T-cell receptor (TCR) signaling. Functional validation and RNA sequencing in Jurkat T cells demonstrate that these mutations induce aberrant T-cell activation in vitro, suggesting a potential mechanistic link to AA pathogenesis. Furthermore, we detect copy number variations in multiple loci containing immune-related genes, which may additionally contribute to disease development. Collectively, our study provides a comprehensive characterization of somatic mutations in a large Chinese AA cohort and elucidates the functional impact of <i>CSK</i> mutations on AA pathogenesis. These findings deepen our understanding of the disease mechanisms underlying AA and identify potential molecular targets for future therapeutic strategies.</p>

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Somatic mutations in CSK disrupt immune regulation in a Chinese aplastic anemia cohort

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月11日

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  • Weirong He,
  • Feifei Li,
  • Liangliang Wu,
  • Xiaoyue Sun,
  • Yuping Zhang,
  • Wenjian Mo,
  • Xiaowei Chen,
  • Zihan Cheng,
  • Xiaopeng Shen,
  • Wenqing Zhang,
  • Zhibin Huang,
  • Shunqing Wang

摘要

Aplastic anemia (AA) is a rare hematological disorder characterized by the failure of bone marrow hematopoiesis. Although somatic mutations are known to play pivotal roles in the pathogenesis and clinical progression of AA, their molecular characteristics in Chinese AA patients remain poorly characterized. In this study, we perform whole-exome sequencing on 126 Chinese AA patients to delineate the somatic mutation landscape. Our analysis reveal recurrently mutated genes enriched in immune regulatory pathways. Notably, we identify eight AA cases harboring mutations in the tyrosine kinase motif of C-terminal Src kinase (CSK), a critical regulator of T-cell receptor (TCR) signaling. Functional validation and RNA sequencing in Jurkat T cells demonstrate that these mutations induce aberrant T-cell activation in vitro, suggesting a potential mechanistic link to AA pathogenesis. Furthermore, we detect copy number variations in multiple loci containing immune-related genes, which may additionally contribute to disease development. Collectively, our study provides a comprehensive characterization of somatic mutations in a large Chinese AA cohort and elucidates the functional impact of CSK mutations on AA pathogenesis. These findings deepen our understanding of the disease mechanisms underlying AA and identify potential molecular targets for future therapeutic strategies.