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<p><i>U2AF1</i> mutations are common in patients with myelodysplastic neoplasms (MDS), suggesting that aberrant splicing of pre-mRNAs driven by mutant U2AF1 could play a critical role in MDS pathogenesis. Previous studies have demonstrated that <i>U2AF1</i><sup><i>S34F</i></sup> mutation impairs the differentiation of erythrocytes and granulocytes, but the impact on megakaryocytes (MKs) remains unclear. Here, by integrating data from MDS patients and cell lines with <i>U2AF1</i> mutations, we determined that <i>U2AF1</i> mutations are associated with dysmegakaryopoiesis, induce the generation of abnormal MKs, especially micro-MKs, and induce significant thrombocytopenia. We determined that mutant U2AF1-mediated aberrant splicing of DNA biosynthesis-related genes, such as <i>CHEK1</i>, is required for normal MK polyploidization. The mis-splicing of <i>CHEK1</i>, in turn, accounts for the increased number of abnormal MKs in U2AF1-mutant MDS patients. Moreover, <i>U2AF1</i><sup><i>S34</i></sup> mutations induce the deficiency of CHK1 and the activation of its phosphorylation, thereby further driving the impairment of MK polyploidization and maturation. Accordingly, treatment with selective CHK1 inhibitor significantly reduces abnormal MK production in vitro. Taken together, these findings demonstrate that <i>U2AF1</i> mutations induce the generation of abnormal MKs by driving aberrant splicing of the <i>CHEK1</i> cell cycle-related gene, revealing the molecular basis for dysmegakaryopoiesis in MDS and identifying a new potential target for MDS treatment.</p>

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Aberrant splicing of CHEK1 is a driver of megakaryocytic dysplasia in U2AF1S34F mutant myelodysplastic neoplasms

  • 期刊论文

  • 发表日期：

    2025年7月12日

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  • Wenjun Zhang,
  • Bing Li,
  • Jinqin Liu,
  • Yiru Yan,
  • Lin Yang,
  • Tiejun Qin,
  • Zefeng Xu,
  • Qi Sun,
  • Yujiao Jia,
  • Huijun Wang,
  • Gang Huang,
  • Hongtao Wang,
  • Lihong Shi,
  • Jiaxi Zhou,
  • Zhijian Xiao

摘要

U2AF1 mutations are common in patients with myelodysplastic neoplasms (MDS), suggesting that aberrant splicing of pre-mRNAs driven by mutant U2AF1 could play a critical role in MDS pathogenesis. Previous studies have demonstrated that U2AF1S34F mutation impairs the differentiation of erythrocytes and granulocytes, but the impact on megakaryocytes (MKs) remains unclear. Here, by integrating data from MDS patients and cell lines with U2AF1 mutations, we determined that U2AF1 mutations are associated with dysmegakaryopoiesis, induce the generation of abnormal MKs, especially micro-MKs, and induce significant thrombocytopenia. We determined that mutant U2AF1-mediated aberrant splicing of DNA biosynthesis-related genes, such as CHEK1, is required for normal MK polyploidization. The mis-splicing of CHEK1, in turn, accounts for the increased number of abnormal MKs in U2AF1-mutant MDS patients. Moreover, U2AF1S34 mutations induce the deficiency of CHK1 and the activation of its phosphorylation, thereby further driving the impairment of MK polyploidization and maturation. Accordingly, treatment with selective CHK1 inhibitor significantly reduces abnormal MK production in vitro. Taken together, these findings demonstrate that U2AF1 mutations induce the generation of abnormal MKs by driving aberrant splicing of the CHEK1 cell cycle-related gene, revealing the molecular basis for dysmegakaryopoiesis in MDS and identifying a new potential target for MDS treatment.