2. Academic Validation
  3. Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms

Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms

  • Nat Commun. 2024 Apr 6;15(1):2989. doi: 10.1038/s41467-024-47297-2.
Peiwen Zhang # 1 2 3,  Na You # 1 2 3,  Yiyi Ding 1 2 3,  Wenqi Zhu 1 2 3,  Nan Wang 1 2 3,  Yueqiao Xie 1 2 3,  Wanling Huang 1 2 3,  Qian Ren 1 2 3,  Tiejun Qin 1 2 3,  Rongfeng Fu 1 2 3,  Lei Zhang 4 5 6,  Zhijian Xiao 7 8 9,  Tao Cheng 10 11 12 13,  Xiaotong Ma 14 15 16
Affiliations

Affiliations

  • 1 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.
  • 2 Tianjin Institutes of Health Science, Tianjin, 301600, China.
  • 3 Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
  • 4 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. zhanglei1@ihcams.ac.cn.
  • 5 Tianjin Institutes of Health Science, Tianjin, 301600, China. zhanglei1@ihcams.ac.cn.
  • 6 Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China. zhanglei1@ihcams.ac.cn.
  • 7 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. zjxiao@ihcams.ac.cn.
  • 8 Tianjin Institutes of Health Science, Tianjin, 301600, China. zjxiao@ihcams.ac.cn.
  • 9 Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China. zjxiao@ihcams.ac.cn.
  • 10 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. chengtao@ihcams.ac.cn.
  • 11 Tianjin Institutes of Health Science, Tianjin, 301600, China. chengtao@ihcams.ac.cn.
  • 12 Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China. chengtao@ihcams.ac.cn.
  • 13 Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China. chengtao@ihcams.ac.cn.
  • 14 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. maxt@ihcams.ac.cn.
  • 15 Tianjin Institutes of Health Science, Tianjin, 301600, China. maxt@ihcams.ac.cn.
  • 16 Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China. maxt@ihcams.ac.cn.
  • # Contributed equally.
PMID: 38582902 DOI: 10.1038/s41467-024-47297-2
Abstract

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.

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