TGF-Β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

• Naka Kazuhito

• Hoshii Takayuki

• Muraguchi Teruyuki

• Tadokoro Yuko

• Ooshio Takako

• Kondo Yukio

• Nakao Shinji

• Motoyama Noboru

• Hirao Atsushi

• 仲 一仁

• 星居 孝之

• 田所 優子

• 大塩 貴子

• 近藤 恭夫

• 中尾 眞二

• 本山 昇

• 平尾 敦

書誌事項

タイトル別名

• Person 人と研究 白血病幹細胞の抗がん剤抵抗性メカニズム
• Person ヒト ト ケンキュウ ハッケツビョウ カンサイボウ ノ コウガンザイ テイコウセイ メカニズム

抄録

金沢大学がん研究所がん幹細胞研究センター

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.

収録刊行物

• Nature

  Nature 463 (7281), 676-680, 2010-02-04

  Nature Publishing Group

詳細情報

• CRID: 1390013408158149632
• NII論文ID: 40018725961
• NII書誌ID: AA00752384
• ISSN: 00280836
• ISSN: 18839053
• DOI: 10.24517/00027379
• NDL書誌ID: 11007516
• Web Site: http://hdl.handle.net/2297/23898
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I11007516
• 本文言語コード: en
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