Eμ/miR-125b transgenic mice develop lethal B-cell malignancies - PubMed (original) (raw)

. 2011 Dec;25(12):1849-56.

doi: 10.1038/leu.2011.166. Epub 2011 Jul 8.

J Kitaura, K Hatakeyama, J Watanuki, T Akasaka, N Kato, M Shimanuki, K Nishimura, M Takahashi, M Taniwaki, C Haferlach, R Siebert, M J S Dyer, N Asou, H Aburatani, H Nakakuma, T Kitamura, T Sonoki

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Eμ/miR-125b transgenic mice develop lethal B-cell malignancies

Y Enomoto et al. Leukemia. 2011 Dec.

Abstract

MicroRNA-125b-1 (miR-125b-1) is a target of a chromosomal translocation t(11;14)(q24;q32) recurrently found in human B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This translocation results in overexpression of miR-125b controlled by immunoglobulin heavy chain gene (IGH) regulatory elements. In addition, we found that six out of twenty-one BCP-ALL patients without t(11;14)(q24;q32) showed overexpression of miR-125b. Interestingly, four out of nine patients with BCR/ABL-positive BCP-ALL and one patient with B-cell lymphoid crisis that had progressed from chronic myelogenous leukemia overexpressed miR-125b. To examine the role of the deregulated expression of miR-125b in the development of B-cell tumor in vivo, we generated transgenic mice mimicking the t(11;14)(q24;q32) (Eμ/miR-125b-TG mice). Eμ/miR-125b-TG mice overexpressed miR-125b driven by IGH enhancer and promoter and developed IgM-negative or IgM-positive lethal B-cell malignancies with clonal proliferation. B cells obtained from the Eμ/miR-125b-TG mice were resistant to apoptosis induced by serum starvation. We identified Trp53inp1, a pro-apoptotic gene induced by cell stress, as a novel target gene of miR-125b in hematopoietic cells in vitro and in vivo. Our results provide direct evidence that miR-125b has important roles in the tumorigenesis of precursor B cells.

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