State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Tianjin Institutes of Health Science, Tianjin, 301600, China.
Nat Commun. 2024 Apr 6;15(1):2989. doi: 10.1038/s41467-024-47297-2.
Despite the identification of driver mutations leading to the initiation of myeloproliferative neoplasms (MPNs), the molecular pathogenesis of MPNs remains incompletely understood. Here, we demonstrate that growth arrest and DNA damage inducible gamma (GADD45g) is expressed at significantly lower levels in patients with MPNs, and JAK2V617F mutation and histone deacetylation contribute to its reduced expression. Downregulation of GADD45g plays a tumor-promoting role in human MPN cells. Gadd45g insufficiency in the murine hematopoietic system alone leads to significantly enhanced growth and self-renewal capacity of myeloid-biased hematopoietic stem cells, and the development of phenotypes resembling MPNs. Mechanistically, the pathogenic role of GADD45g insufficiency is mediated through a cascade of activations of RAC2, PAK1 and PI3K-AKT signaling pathways. These data characterize GADD45g deficiency as a novel pathogenic factor in MPNs.
尽管已经确定了导致骨髓增生性肿瘤（MPN）发生的驱动突变，但 MPN 的分子发病机制仍不完全清楚。在这里，我们证明生长停滞和 DNA 损伤诱导的 γ（GADD45g）在 MPN 患者中的表达水平显著降低，JAK2V617F 突变和组蛋白去乙酰化导致其表达减少。GADD45g 的下调在人类 MPN 细胞中发挥促肿瘤作用。单独在小鼠造血系统中缺乏 Gadd45g 会导致偏骨髓造血干细胞的生长和自我更新能力显著增强，并发展出类似于 MPN 的表型。从机制上讲，GADD45g 不足的致病作用是通过 RAC2、PAK1 和 PI3K-AKT 信号通路的级联激活来介导的。这些数据表明 GADD45g 缺乏是 MPN 的一种新的致病因素。
