Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21558-63. doi: 10.1073/pnas.1016611107. Epub 2010 Nov 30.
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.
miR-125b 在多种白血病中被涉及。在骨髓增生异常和急性髓细胞白血病患者中发现的染色体易位 t(2;11)(p21;q23)导致 miR-125b 的过度表达高达正常的 90 倍。此外，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，miR-125b 也被上调。为了解释 miR-125b 的假定致癌机制，我们在小鼠中进行了移植实验。所有移植了异位表达 miR-125b 的胎肝细胞的小鼠都表现出白细胞计数增加，特别是中性粒细胞和单核细胞增加，伴有巨红细胞性贫血。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-125b 在早期造血中具有重要作用。此外，与仅表达 BCR-ABL 的对照小鼠相比，在移植细胞中共同表达 miR-125b 和 BCR-ABL 融合基因加速了小鼠白血病的发展，这表明 miR-125b 赋予白血病细胞增殖优势。因此，我们表明 miR-125b 的过度表达足以缩短 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。
