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Updated: Jun 29, 2025
Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms
Peiwen Zhang1,2,3, Na You1,2,3, Yiyi Ding1,2,3
1State 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.
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.
Insights
Reduced growth arrest and DNA damage inducible gamma (GADD45g) expression promotes myeloproliferative neoplasms (MPNs). GADD45g deficiency enhances stem cell growth and drives MPN development via specific signaling pathways.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Myeloproliferative neoplasms (MPNs) are driven by mutations, but their full molecular pathogenesis is unclear.
- Growth arrest and DNA damage inducible gamma (GADD45g) is a gene involved in cellular stress responses.
Purpose of the Study:
- To investigate the role of GADD45g in the molecular pathogenesis of MPNs.
- To determine if GADD45g deficiency contributes to MPN development and progression.
Main Methods:
- Analyzed GADD45g expression levels in MPN patients.
- Investigated the effects of JAK2V617F mutation and histone deacetylation on GADD45g expression.
- Utilized a murine model with Gadd45g insufficiency in hematopoietic stem cells.
- Examined the activation of RAC2, PAK1, and PI3K-AKT signaling pathways.
Main Results:
- GADD45g is significantly downregulated in MPN patients.
- JAK2V617F mutation and histone deacetylation reduce GADD45g expression.
- Gadd45g insufficiency in mice enhances myeloid-biased hematopoietic stem cell growth and self-renewal, leading to MPN-like phenotypes.
- GADD45g deficiency activates RAC2, PAK1, and PI3K-AKT pathways, promoting tumor growth.
Conclusions:
- GADD45g deficiency is a novel pathogenic factor in MPNs.
- Reduced GADD45g expression promotes MPN development by enhancing stem cell function and activating key signaling pathways.
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