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Although driver mutations in myeloproliferative neoplasms (MPNs) have been identified, the molecular pathogenesis of MPNs remains incomplete.
On April 6, 2024, Xiaotong Ma, Tao Cheng, Zhijian Xiao and Lei Zhang jointly published a paper titled "Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms" in Nature Communications. The study demonstrated that growth arrest and DNA damage-induced γ (GADD45g) expression levels were significantly reduced in MPN patients, and that JAK2V617F mutations and histone deacetylation led to a decrease in its expression.
Downregulation of GADD45g plays a tumor-promoting role in human MPN cells. Gadd45g insufficiency in the murine hematopoietic system alone results in a significant increase in the growth and self-renewal capacity of biased myeloid hematopoietic stem cells, as well as the development of a phenotype similar to MPN. Mechanistically, the pathogenic effects of GADD45g deficiency are mediated by activation of RAC2, PAK1 and PI3K-AKT signaling pathways. These data suggest that GADD45g deficiency is a novel pathogenic factor for MPN.
Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell (HSC) diseases that affect myelopathic cells. Classical Philadelphia-negative MPN PhMPN) is characterized by excessive output from one or more mature myeloid lineages, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Mutations in JAK2, CALR, and MPL, known as "driver mutations," occur in more than 95% of patients with MPN, resulting in constitutive activation of the JAK-STAT signaling pathway, which then leads to disease. In addition, in patients with MPN, co-occurring somatic mutations in genes associated with epigenetic regulation, transcriptional control, and splicing machines have been found to precede driver mutations and lead to disease progression. Among them, ASXL1, DNMT3A and TET2 are at relatively high frequencies in more than 5% of patient samples across the entire MPNs spectrum. Current treatments have shown benefits in reducing splenomegaly and improving symptoms in patients with MPN. However, they are not effective in eradicating MPNs stem cells, and the molecular response is variable and unpredictable. A better understanding of the pathogenesis of MPN may provide new targets for the development of effective therapeutics. The GADD45 gene family encoding small (18 kDa) nuclear/cytoplasmic proteins (GADD45a, GADD45b, and GADD45g) is a stress sensor. Previous studies have shown that GADD45g preferentially silences in patients with acute myeloid leukemia (AML), and its upregulation exerts selective and potent antileukemic effects. However, it is still unknown whether GADD45g will play a role in the development of MPN. The study found that GADD45g expression was significantly reduced in MPN patients and was negatively correlated with higher clonogenic potential and inflammatory cytokine production. Lack of Gadd45g alone is sufficient to induce MPN in mice. GADD45g deficiency exerts tumor-promoting activity by activating the RAC2-PAK1-PI3K-AKT signaling pathway. The most common driver mutations JAK2V617F and histone deacetylation are associated with GADD45g silencing in MPN. This study is the first to demonstrate the pathogenic role of GADD45g insufficiency in MPNs.
降低人MPNs细胞中GADD45g的表达具有促进肿瘤的功能（Credit: Nature Communications）
In summary, this study demonstrates for the first time that GADD45g insufficiency is a novel causative agent of MPN that works by activating the RAC2-PAK1-PI3K-AKT cascade. Low expression of GADD45g in MPN is associated with JAK2V617F mutations and histone deacetylation. The Gadd45g deletion mouse model established in this study not only provides a valuable platform for revealing the molecular basis of disease occurrence and progression, but also provides a valuable platform for patients to develop new treatments.
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Hatps://doi.org/10.1038/s41467-024-47297-2
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文章来源|“ iNature"
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