Suppression of the let-7b microRNA pathway by DNA hypermethylation in infant acute lymphoblastic leukemia with MLL gene rearrangements
Suppression of the let-7b microRNA pathway by DNA hypermethylation in infant acute lymphoblastic leukemia with MLL gene rearrangements
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DOI：
10.1038/leu.2012.242
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发表时间：
2013-02-01
期刊：
影响因子：
11.4
通讯作者：
Eguchi, M.
中科院分区：
文献类型：
--
作者：
Nishi, M.;Eguchi-Ishimae, M.;Eguchi, M.
microRNAs（miRNAs）通过控制参与多种信号通路的蛋白质的表达来调节细胞的增殖和分化。最近的研究表明，在几种类型的癌症中，miRNA表达失调与致瘤性增加和预后不良相关。miRNA let-7 b是混合系白血病（MLL）重排的急性淋巴细胞白血病（ALL）患者中严重下调的miRNA之一。致白血病MLL融合基因体外转染人胚肾-293细胞抑制let-7 b表达。在具有MLL融合基因的白血病细胞中，let-7 b表达的调节区被高甲基化，并且在用去甲基化剂5-阿扎胞苷培养细胞后其表达部分恢复。这些结果表明，let-7 b表达的损失可能是致癌MLL融合蛋白的后果之一，并有助于白血病可能通过上调let-7 b调节的靶基因与造血细胞中的白血病发生潜力。在ALL细胞系中，MLL融合基因的let-7 b的强制表达抑制了它们的生长，这表明let-7 b可能用作MLL融合基因难治性婴儿ALL的新治疗工具。白血病（2013）27，389-397; doi：10.1038/leu.2012.242
MicroRNAs (miRNAs) regulate cell proliferation and differentiation by controlling the expression of proteins involved in many signaling pathways. Recent studies have shown that dysregulation of miRNA expression is associated with increased tumorigenicity and a poor prognosis in several types of cancers. The miRNA let-7b is one of the severely downregulated miRNAs in mixed-lineage leukemia (MLL)-rearranged acute lynnphoblastic leukemia (ALL) patients. In vitro transfection of leukemogenic MLL fusion genes into human embryonic kidney-293 cells suppressed let-7b expression. In leukemic cells with an MLL fusion gene, the regulatory region for let-7b expression was hypermethylated, and its expression was partially recovered after culturing the cells with the demethylating agent 5-azacitidine. These results suggest that loss of let-7b expression may be one of the consequences of oncogenic MLL fusion proteins, and contributes to leukemogenesis possibly through the upregulation of let-7b-regulated target genes with leukemogenic potential in hematopoietic cells. The enforced expression of let-7b in ALL cell lines with an MLL fusion gene inhibited their growth, indicating the possible use of let-7b as a new therapeutic tool for refractory infant ALL with an MLL fusion gene. Leukemia (2013) 27, 389-397; doi:10.1038/leu.2012.242