Department of Pediatrics, Saga University, Saga, Japan.
Leukemia. 2013 Feb;27(2):389-97. doi: 10.1038/leu.2012.242. Epub 2012 Aug 24.
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 lymphoblastic 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.
微小 RNA（miRNAs）通过控制参与许多信号通路的蛋白质的表达来调节细胞增殖和分化。最近的研究表明，miRNA 表达失调与几种癌症的肿瘤发生增加和预后不良有关。miRNA let-7b 是混合谱系白血病（MLL）重排急性淋巴细胞白血病（ALL）患者中严重下调的 miRNA 之一。将致白血病 MLL 融合基因体外转染入人胚肾-293 细胞中，抑制了 let-7b 的表达。在具有 MLL 融合基因的白血病细胞中，let-7b 表达的调节区发生超甲基化，在用去甲基化剂 5-氮杂胞苷培养细胞后，其表达部分恢复。这些结果表明，let-7b 表达的丧失可能是致癌性 MLL 融合蛋白的后果之一，并且可能通过上调造血细胞中具有致白血病潜能的 let-7b 调节靶基因来促进白血病发生。在具有 MLL 融合基因的 ALL 细胞系中强制表达 let-7b 抑制了它们的生长，表明 let-7b 可能作为一种新的治疗工具用于难治性婴儿 ALL 伴 MLL 融合基因。
