Researchers from Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine confirmed that DNA methyltransferases 3A (DNMT3A) Arg882 mutation in hematopoietic cells drives chronic granulocytes by disrupting gene expression / DNA methylation Leukemia (Chronic myelomonocytic leukemia, CMML). The results of this study were published in the journal Proceedings of the American Academy of Sciences (PNAS) on February 4.
Academicians Zhu Chen, Sai-Juan Chen and Dr. Yue-Ying Wang of Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine are co-corresponding authors of this paper.
CMML is a chronic myeloid leukemia. The incidence rate is about 1 to 2 / 100,000 per year, most of which will occur after the age of 60, and the male to female incidence rate is about 1.5 to 3: 1. The specific cause is unknown. There is no specific chromosomal ectopic. Common clinical symptoms include fever, infection, bleeding, fatigue, weight loss, and night sweats. About half of the patients have hepatosplenomegaly. The median survival time of CMML patients is about 20 months, and the survival time may be related to the proportion of bone marrow blasts. There is currently no specific treatment.
DNMT3A is one of the DNA methyltransferases with catalytic activity in mammals, mainly plays a de novo methylation role, and is an important molecule in the study of tumor epigenetic mechanism in recent years. In the process of epigenetic regulation of tumor-related genes, DNMT3A can directly perform the catalytic function to methylate the CpG island of the target gene promoter to achieve methylation status changes to achieve transcription silencing effect; Domains and related factors work together to achieve specific methylation patterns.
In 2011, a team of academicians Chen Zhu and Chen Saijuan published a paper in the journal Nature Genetics, claiming that DNMT3A was found in acute myeloid leukemia M5 (also known as acute monocytic leukemia, AML-M5) High frequency mutation. In addition, 13.6% of patients with acute myeloid leukemia M4 type DNMT3A Arg882 changed. Therefore, it is confirmed that the abnormal activity of this DNA methyltransferase is closely related to acute myeloid leukemia, which provides a potential biomarker for the diagnosis and prognosis evaluation of the disease. However, up to now, the researchers still do not know the role and mechanism of the mutation DNMT3A in hematopoiesis.
In this new PNAS article, the researchers used a retrovirus transduction and bone marrow transplantation (BMT) to reveal the transforming ability of the DNMT3A-Arg882His (R882H) mutant, confirming that this mutation can induce hematopoietic stem / progenitor cell abnormalities proliferation. After 12 months of BMT, all mice developed CMML. The results of RNA microarray analysis revealed the abnormal expression of some genes related to hematopoiesis, and DNA methylation analysis revealed changes in the corresponding methylation patterns in the gene body region. The DNMT3A R882 mutation drives CMML by increasing CDK1 protein levels in hematopoietic cells, disrupting transcriptional expression / DNA methylation procedures, and cell cycle regulation.
These findings clarify the function of DNMT3A mutation in myeloid leukemia.
Splash Series,Splash Toys,Inflatable Splash Pad,Splash Mat
P&D Plastic Manufacture Co., Ltd , https://www.pdinflatable.com