On April 6th, researchers including Dr. Ma Xiaotong, Professor Cheng Tao, Dr. Xiao Zhijian, and Chief Physician Zhang Lei from the Hematology Hospital of the Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences) published a study in Nature Communications. It unveiled, for the first time, that the silencing of the GADD45g gene is a novel pathogenic factor in myeloproliferative neoplasms (MPNs). The study elucidated the downstream molecular mechanisms of GADD45g action and the mechanism of its low expression in patient cells, providing a new target for the development of novel MPN therapeutics.
Myeloproliferative neoplasms (MPNs) are a group of heterogeneous clonal proliferative disorders of hematopoietic stem cells. Classic BCR-ABL fusion gene-negative MPNs manifest as uncontrolled proliferation of myeloid or multiple hematopoietic cell lineages, including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Mutations in JAK2, CALR, and MPL genes occur in up to 90% of MPN patients and have long been considered driver mutations in MPNs.
However, current MPN therapies, such as JAK2 inhibitors, only alleviate patients' clinical symptoms and fail to achieve molecular remission by effectively eliminating MPN stem cells. Therefore, delving into the pathogenesis of MPNs can provide new targets for developing more effective therapeutic drugs.
To this end, researchers have discovered through a series of scientific experiments that the GADD45g gene is significantly underexpressed in bone marrow cells of MPN patients and exerts anti-cancer effects. To understand its role in pathogenesis due to its underexpression, researchers constructed Gadd45g hematopoietic system-specific knockout mice models, both homozygous and heterozygous.
The results revealed progressive changes in the knockout mice hematopoietic system over time. At 4 months, the self-renewal capacity of long-term hematopoietic stem cells (LT-HSCs) in knockout mice was significantly enhanced. By 6 months, the hematopoietic system gradually skewed towards myelopoiesis, with an increased number of hematopoietic stem cells (HSCs) and further enhancement of self-renewal capacity, primarily in myeloid-biased HSCs. After 10 months, the mice developed MPN.
Furthermore, transplanting bone marrow from diseased mice could still induce MPN, and repletion of Gadd45g significantly prolonged mouse survival and reduced the incidence of the disease, confirming that underexpression of Gadd45g in the hematopoietic system of mice indeed induces MPN.
Subsequently, researchers, through transcriptome sequencing (RNA-seq) and mass spectrometry, first discovered that under normal conditions, GADD45g binds to RAC2 and inhibits its activity. Underexpression of GADD45g in MPN cells leads to its dissociation from RAC2, relieving the inhibition of RAC2 activity. Activated RAC2 binds to PAK1, activating PAK1, which in turn activates the PI3K/AKT pathway, leading to the induction of MPN. Whole-exome sequencing results showed that Gadd45g knockout did not induce significant mutations in important myeloid tumor-related genes.
Moreover, the study also found that chronic inflammation is a key feature of MPNs, with high levels of inflammatory factors involved in disease progression. Testing Gadd45g knockout mice revealed abnormal elevation of some inflammatory factors, consistent with clinical observations. Levels of IL-4 and IL-6 in MPN patients were negatively correlated with GADD45g expression levels, indicating that GADD45g silencing contributes to the upregulation of inflammatory factors in MPN. Further exploration of the upstream regulatory mechanism of GADD45g expression confirmed that MPN driver mutation JAK2V617F and histone deacetylation jointly lead to GADD45g gene silencing.
The researchers stated that this study helps deepen the understanding of the pathogenesis of MPNs and provides important theoretical basis for discovering new clinical treatment targets. Ma Xiaotong, Cheng Tao, Xiao Zhijian, and Zhang Lei are co-corresponding authors. Zhang Peiwen and You Na, doctoral students at the Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences), are co-first authors. This project was supported by the Medical and Health Technology Innovation Engineering of the Chinese Academy of Medical Sciences and the National Natural Science Foundation of China.
Related paper information: https://doi.org/10.1038/s41467-024-47297-2
