A study published in Nature Communications reveals for the first time that GADD45g gene silencing is a new pathogenic factor for myeloproliferative tumors (MPN), clarifying the downstream molecular mechanisms of GADD45g action and its low expression in patient cells.
Myeloproliferative tumors are a group of heterogeneous cloned hematopoietic stem cell diseases.The classical BCR-ABL fusion gene negative MPN showed uncontrolled proliferation of one or more lines of myeloid cells, including true erythrocytosis, primary thrombocytopenia and primary myelofibrosis.Mutations in the JAK2, CALR and MPL genes occur in up to 90% of patients with MPN and have been thought to be the cause of MPN for the past few decades, known as driver mutations.
However, the existing MPN treatment drug JAK2 inhibitors can only relieve patients' clinical symptoms and cannot achieve molecular remission by effectively removing MPN tumor stem cells.Therefore, in-depth study of the pathogenesis of MPN can provide a new target for the development of more effective therapeutic drugs.
To this end, the researchers found through a series of scientific experiments that the GADD45g gene was significantly lower in bone marrow cells in MPN patients and played a cancer-suppressing role.In order to understand the in vivo pathogenic effect of low expression, the researchers constructed a pure, heterozygous knockout mouse model of Gadd45g hematopoietic system specificity.
The results showed that the hematopoietic system of knockout mice gradually changed with time.At 6 months, the hematopoietic system gradually partialized the hematopoietic stem cells (HSCs) and the number of hematopoietic stem cells (HSCs) increased.
Furthermore, MPN could be induced after bone marrow transplantation, and Gadd45g supplementation significantly prolonged the survival period and reduced the incidence of Gadd45g.
Subsequently, through transcriptome sequencing (RNA-seq) and mass spectrometry, the researchers found for the first time that GADD45g expression normally binds to RAC2 and inhibits RAC2 activity.The low expression of GADD45g in MPN cells led to dissociation from RAC2 and the inhibition of RAC2 activity was also removed; activated RAC2 and PAK1 combined to activate PAK1, which led to activation of PI3K/AKT pathway and induced MPN.Full exon sequencing showed that Gadd45g knock-out did not trigger a significant myeloid tumor-associated gene mutation.
In addition, the study found that chronic inflammation is an important feature of MPN and that high levels of inflammatory factors are involved in disease progression.The results showed that IL-4 and IL-6 levels in MPN patients were negatively correlated with GADD45g expression, indicating that GADD45g silence was involved in the increase of MPN inflammatory factor expression.Further exploration of upstream regulatory mechanisms of GADD45g expression confirmed that MPN-driven mutation JAK2V617F and histone deacetylation resulted in GADD45g gene silencing.
The researchers said the study could help to gain an in-depth understanding of the pathogenesis of MPN and provide important theoretical basis for the discovery of new clinical therapeutic targets.Ma Xiaotong, Cheng Tao, Xiao Zhijian and Zhang Lei are co-authors.Zhang Peiwen and Yuna, Ph.D. students at the Hospital of Hematology of the Chinese Academy of Medical Sciences (Institute of Hematology of the Chinese Academy of Medical Sciences), are co-first authors.The project won the support of the Chinese Academy of Medical Sciences and Health Science Innovation Engineering and the National Natural Science Foundation.