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タイトル: TGF-Β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia
著者: Naka, Kazuhito
Hoshii, Takayuki
Muraguchi, Teruyuki
Tadokoro, Yuko
Ooshio, Takako
Kondo, Yukio link image link image
Nakao, Shinji link image link image
Motoyama, Noboru
Hirao, Atsushi link image link image
仲, 一仁
田所, 優子
近藤, 恭夫
中尾, 眞二
発行日: 2010年 2月 4日
出版社(者): Nature Publishing Group
雑誌名: Nature
ISSN: 0028-0836
巻: 463
号: 7281
開始ページ: 676
終了ページ: 680
抄録: Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a+/+ and Foxo3a-/- mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-Β is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-Β inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-Β inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-Β-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo. © 2010 Macmillan Publishers Limited. All rights reserved.
DOI: 10.1038/nature08734
URI: http://hdl.handle.net/2297/23898
資料種別: Journal Article
版表示: author
出現コレクション:1. 査読済論文

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