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Animal Models

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

Leukemia volume 25, pages 1849–1856 (2011)Cite this article

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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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Acknowledgements

We thank Dr Kiwamu Akagi (Saitama Cancer Institute, Japan) for providing the pEμ/IGH plasmid, Dr Hiroshi Matsuoka (Kobe University, Japan) for helpful discussion and Dr Dovie Wylie for her excellent language support. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, and was in part supported by Grant-in-Aid for Scientific Research on Innovative Areas, Global COE Program ‘Center of Education and Research for the Advanced Genome-Based Medicine—For personalized medicine and the control of worldwide infectious diseases’, MEXT, Japan, Grant for Basic and Clinical Research Project from Osaka Cancer Research Foundation 2008, A Research Grant on Priority Areas from Wakayama Medical University 2008, and a grant from the Japan Society for the Promotion Science (JSPS). This work was performed in the Cooperative Research Project of the Institute of Medical Science, Tokyo University. YE is a JSPS research fellow.

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Authors and Affiliations

  1. Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Y Enomoto, J Kitaura, N Kato, K Nishimura, M Takahashi & T Kitamura

  2. Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    K Hatakeyama

  3. Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

    J Watanuki, M Shimanuki, H Nakakuma & T Sonoki

  4. MRC Toxicology Unit/University of Leicester, Leicester, UK

    T Akasaka & M J S Dyer

  5. Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan

    M Taniwaki

  6. MLL Münchner Leukämielabor GmbH Max-Lebsche-Platz, München, Germany

    C Haferlach

  7. Institute of Human Genetics, Christian-Albrechts-University Kiel/University Hospital Schleswig-Holstein, Kiel, Germany

    R Siebert

  8. Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan

    N Asou

  9. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

    H Aburatani

  10. Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    T Kitamura

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  1. Y Enomoto
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Correspondence to T Kitamura or T Sonoki.

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Enomoto, Y., Kitaura, J., Hatakeyama, K. et al. Eμ/miR-125b transgenic mice develop lethal B-cell malignancies. Leukemia 25, 1849–1856 (2011). https://doi.org/10.1038/leu.2011.166

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