Zhang Wenjun, Li Bing, Liu Jinqin, Yan Yiru, Yang Lin, Qin Tiejun, Xu Zefeng, Sun Qi, Jia Yujiao, Wang Huijun, Huang Gang, Wang Hongtao, Shi Lihong, Zhou Jiaxi, Xiao Zhijian
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Leukemia. 2025 Jul 12. doi: 10.1038/s41375-025-02684-6.
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 U2AF1 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, U2AF1 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.
U2AF1突变在骨髓增生异常肿瘤（MDS）患者中很常见，这表明由突变型U2AF1驱动的前体mRNA异常剪接可能在MDS发病机制中起关键作用。先前的研究表明，U2AF1突变会损害红细胞和粒细胞的分化，但对巨核细胞（MKs）的影响仍不清楚。在这里，通过整合来自MDS患者和具有U2AF1突变的细胞系的数据，我们确定U2AF1突变与巨核细胞生成异常有关，可诱导异常MKs的产生，尤其是微小MKs，并导致显著的血小板减少。我们确定，突变型U2AF1介导的DNA生物合成相关基因（如CHEK1）的异常剪接是正常MK多倍体化所必需的。反过来，CHEK1的错误剪接导致U2AF1突变的MDS患者中异常MKs数量增加。此外，U2AF1突变导致CHK1缺乏及其磷酸化激活，从而进一步加剧MK多倍体化和成熟的损害。因此，用选择性CHK1抑制剂治疗可显著减少体外异常MK的产生。综上所述，这些发现表明，U2AF1突变通过驱动CHEK1细胞周期相关基因的异常剪接诱导异常MKs的产生，揭示了MDS中巨核细胞生成异常的分子基础，并确定了MDS治疗的一个新的潜在靶点。
