Loss of Dnmt3b accelerates MLL-AF9 leukemia progression
Loss of Dnmt3b accelerates MLL-AF9 leukemia progression
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Dnmt3b 缺失加速 MLL-AF9 白血病进展
DOI：
10.1038/leu.2016.112
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发表时间：
2016-12-01
期刊：
影响因子：
11.4
通讯作者：
Cheng, T.
中科院分区：
文献类型：
--
作者：
Zheng, Y.;Zhang, H.;Cheng, T.
急性髓细胞白血病（AML）是一种异质性造血系统疾病，预后差. DNA甲基化异常参与AML的发生和发展。从头甲基转移酶Dnmt 3a和Dnmt 3b负责基因组甲基化模式的产生。虽然DNMT 3A在血液恶性肿瘤中经常突变，但DNMT 3B很少突变。尽管先前已经报道了Dnmt 3b在Myc诱导的淋巴瘤发生的小鼠模型中作为肿瘤抑制因子发挥作用，但其在AML中的功能尚未确定。在这项研究中，我们证明了Dnmt 3b的缺失通过增加干细胞性和增强细胞周期进程来加速MLL-AF 9白血病的进展。基因谱分析显示致癌基因组上调和细胞分化基因组下调。此外，Dnmt 3b的缺失能够与Dnmt 3a缺陷在白血病发展中协同作用。总之，这些结果表明，Dnmt 3b在MLL-AF 9 AML进展中发挥肿瘤抑制作用，从而为DNA甲基化在白血病发展中的作用提供了新的见解。
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic disorder with a poor prognosis. Abnormal DNA methylation is involved in the initiation and progression of AML. The de novo methyltransferases Dnmt3a and Dnmt3b are responsible for the generation of genomic methylation patterns. While DNMT3A is frequently mutated in hematological malignancies, DNMT3B is rarely mutated. Although it has been previously reported that Dnmt3b functions as a tumor suppressor in a mouse model of Myc-induced lymphomagenesis, its function in AML is yet to be determined. In this study, we demonstrated that deletion of Dnmt3b accelerated the progression of MLL-AF9 leukemia by increasing stemness and enhancing cell cycle progression. Gene profiling analysis revealed upregulation of the oncogenic gene set and downregulation of the cell differentiation gene set. Furthermore, loss of Dnmt3b was able to synergize with Dnmt3a deficiency in leukemia development. Taken together, these results demonstrate that Dnmt3b plays a tumor suppressive role in MLL-AF9 AML progression, thereby providing new insights into the roles of DNA methylation in leukemia development.