MicroRNA miR-125b causes leukemia
MicroRNA miR-125b causes leukemia
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DOI：
10.1073/pnas.1016611107
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发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Lodish, Harvey F.
中科院分区：
文献类型：
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作者：
Bousquet, Marina;Harris, Marian H.;Lodish, Harvey F.
microRNA miR-125 b与几种白血病有关。在骨髓增生异常和急性髓性白血病患者中发现的染色体易位t（2;11）（p21;q23）导致miR-125 b过表达高达正常值的90倍。此外，miR-125 b在携带t（11;14）（q24;q32）易位的B细胞急性淋巴细胞白血病患者中也上调。为了破译miR-125 b的假定致癌机制，我们在小鼠中进行了移植实验。所有移植有异位表达miR-125 b的胎肝细胞的小鼠均显示出与大红细胞性贫血相关的白色血细胞计数增加，特别是中性粒细胞和单核细胞。在这些小鼠中，有一半死于B细胞急性淋巴细胞白血病、T细胞急性淋巴细胞白血病或骨髓增生性肿瘤，这表明miR-125 b在早期造血中发挥重要作用。此外，与仅表达BCR-ABL的对照小鼠相比，移植细胞中miR-125 b和BCR-ABL融合基因的共表达加速了小鼠白血病的发展，表明miR-125 b赋予白血病细胞增殖优势。因此，我们发现miR-125 b的过表达足以缩短BCR-ABL诱导的白血病的潜伏期，并在小鼠模型中独立诱导白血病。
MicroRNA miR-125b has been implicated in several kinds of leukemia. The chromosomal translocation t(2;11)(p21;q23) found in patients with myelodysplasia and acute myeloid leukemia leads to an overexpression of miR-125b of up to 90-fold normal. Moreover, miR-125b is also up-regulated in patients with B-cell acute lymphoblastic leukemia carrying the t(11;14)(q24;q32) translocation. To decipher the presumed oncogenic mechanism of miR-125b, we used transplantation experiments in mice. All mice transplanted with fetal liver cells ectopically expressing miR-125b showed an increase in white blood cell count, in particular in neutrophils and monocytes, associated with a macrocytic anemia. Among these mice, half died of B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, or a myeloproliferative neoplasm, suggesting an important role for miR-125b in early hematopoiesis. Furthermore, coexpression of miR-125b and the BCR-ABL fusion gene in transplanted cells accelerated the development of leukemia in mice, compared with control mice expressing only BCR-ABL, suggesting that miR-125b confers a proliferative advantage to the leukemic cells. Thus, we show that overexpression of miR-125b is sufficient both to shorten the latency of BCR-ABL-induced leukemia and to independently induce leukemia in a mouse model.