Lin Na, Fu Wei, Zhao Chen, Li Bixin, Yan Xiaojing, Li Yan
Department of Hematology, The First Affiliated Hospital of China Medical University, Shenyang, China.
Department of Hematology, The First Affiliated Hospital of China Medical University, Shenyang, China.
Biochem Biophys Res Commun. 2017 Dec 9;494(1-2):270-277. doi: 10.1016/j.bbrc.2017.10.041. Epub 2017 Oct 9.
DNA methyltransferase 3A (DNMT3A) catalyzes de novo DNA methylation and plays important roles in the pathogenesis of acute myeloid leukemia. However, the expression status of DNMT3A variants in acute myeloid leukemia remains obscure. This study aimed to assess the expression levels of alternative splicing of DNMT3A variants and explore their roles in acute myeloid leukemia (AML). DNMT3A variants gene expression were assessed, measuring their effects on cell proliferation. In addition, the expression of DNMT3A variants were evaluated in acute myeloid leukemia patients. Four DNMT3A variants were identified, with DNMT3A1 and DNMT3A2V found to be dominant in acute myeloid leukemia cell lines. Moreover, DNMT3A2V overexpression delayed cell proliferation; while, DNMT3A2V R882H mutation promoted cell proliferation. Further, DNMT3A1 and DNMT3A2V were detected in newly diagnosed acute myeloid leukemia (AML) patients and controls with non-malignant hematological disease, with DNMT3A2V significantly up-regulated in AML patients. The main transcript switched from DNMT3A1 to DNMT3A2V in some patients, especially the low risk group based on the NCCN 2016 guidelines. These findings suggest that DNMT3A1 and DNMT3A2V are the main variants in acute myeloid leukemia with different clinical association, and might play important roles in the pathophysiology of acute myeloid leukemia.
DNA甲基转移酶3A（DNMT3A）催化DNA从头甲基化，并在急性髓系白血病的发病机制中发挥重要作用。然而，DNMT3A变体在急性髓系白血病中的表达状态仍不清楚。本研究旨在评估DNMT3A变体的可变剪接表达水平，并探讨它们在急性髓系白血病（AML）中的作用。评估了DNMT3A变体基因表达，测量它们对细胞增殖的影响。此外，还评估了急性髓系白血病患者中DNMT3A变体的表达。鉴定出四种DNMT3A变体，发现DNMT3A1和DNMT3A2V在急性髓系白血病细胞系中占主导地位。此外，DNMT3A2V过表达延迟细胞增殖；而DNMT3A2V R882H突变促进细胞增殖。进一步地，在新诊断的急性髓系白血病（AML）患者和非恶性血液病对照中检测到DNMT3A1和DNMT3A2V，DNMT3A2V在AML患者中显著上调。在一些患者中，主要转录本从DNMT3A1转换为DNMT3A2V，尤其是根据2016年NCCN指南的低风险组。这些发现表明，DNMT3A1和DNMT3A2V是急性髓系白血病中的主要变体，具有不同的临床关联，可能在急性髓系白血病的病理生理学中发挥重要作用。
