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

N. Tatsumi, N. Hojo, O. Yamada, M. Ogawa, Y. Katsura, S. Kawata, E. Morii, H. Sakamoto, R. Inaba, A. Tsuda, I. Fukuda, N. Moriguchi, H. Hasuwa, M. Okabe, F. Fujiki, S. Nishida, H. Nakajima, A. Tsuboi, Y. Oka, N. HosenH. Sugiyama, Y. Oji

研究成果: Article査読

11 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1003-1014
ページ数12
ジャーナルOncogene
35
8
DOI
出版ステータスPublished - 2016 2月 25
外部発表はい

ASJC Scopus subject areas

  • 分子生物学
  • 遺伝学
  • 癌研究

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