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Deficiency in WT1-targeting microRNA-125a leads to myeloid malignancies and urogenital abnormalities

Oncogene volume 35, pages 1003–1014 (2016)Cite this article

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Abstract

The Wilms’ tumor gene WT1 is overexpressed in leukemia and solid tumors and has an oncogenic role in leukemogenesis and tumorigenesis. However, precise regulatory mechanisms of WT1 overexpression remain undetermined. In the present study, microRNA-125a (miR-125a) was identified as a miRNA that suppressed WT1 expression via binding to the WT1-3’UTR. MiR-125a knockout mice overexpressed WT1, developed myeloproliferative disorder (MPD) characterized by expansion of myeloid cells in bone marrow (BM), spleen and peripheral blood, and displayed urogenital abnormalities. Silencing of WT1 expression in hematopoietic stem/progenitor cells of miR-125a knockout MPD mice by short-hairpin RNA inhibited myeloid colony formation in vitro. Furthermore, the incidence and severity of MPD were lower in miR-125a (−/−) mice than in miR-125a (+/−) mice, indicating the operation of compensatory mechanisms for the complete loss of miR-125a. To elucidate the compensatory mechanisms, miRNA array was performed. MiR-486 was occasionally induced in compete loss of miR-125a and inhibited WT1 expression instead of miR-125a, resulting in the cancellation of MPD occurrence. These results showed for the first time the post-transcriptional regulatory mechanisms of WT1 by both miR-125a and miR-486 and should contribute to the elucidation of mechanisms of normal hematopoiesis and kidney development.

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Acknowledgements

This work was supported in part by a Grant-in-Aid from the Ministry of Education, Science, Sports, Culture and Technology, Japan, and the Ministry of Health, Labour, and Welfare, Japan. We thank Yoko Esaki and Saki Nishioka of NPO Biotechnology Research and Development for technical assistance.

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Authors and Affiliations

  1. Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    N Tatsumi, N Hojo, O Yamada, M Ogawa, Y Katsura, S Kawata, H Sakamoto, R Inaba, A Tsuda, I Fukuda, N Moriguchi & H Sugiyama

  2. Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    E Morii

  3. Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

    H Hasuwa & M Okabe

  4. Department of Cancer Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    F Fujiki, H Nakajima & Y Oka

  5. Department of Respiratory Medicine, Immunology and Allergy, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    S Nishida

  6. Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    A Tsuboi

  7. Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    N Hosen & Y Oji

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Tatsumi, N., Hojo, N., Yamada, O. et al. Deficiency in WT1-targeting microRNA-125a leads to myeloid malignancies and urogenital abnormalities. Oncogene 35, 1003–1014 (2016). https://doi.org/10.1038/onc.2015.154

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