Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL

  1. Sahoko Matsuoka1,2,
  2. Yuichi Oike1,3,4,13,
  3. Ichiro Onoyama5,
  4. Atsushi Iwama6,7,
  5. Fumio Arai1,
  6. Keiyo Takubo1,
  7. Yoichi Mashimo8,
  8. Hideyuki Oguro7,
  9. Eriko Nitta1,
  10. Keisuke Ito1,2,
  11. Kana Miyamoto1,
  12. Hiroki Yoshiwara1,
  13. Kentaro Hosokawa1,
  14. Yuka Nakamura1,
  15. Yumiko Gomei1,
  16. Hiroko Iwasaki1,
  17. Yasuhide Hayashi9,
  18. Yumi Matsuzaki10,
  19. Keiko Nakayama11,
  20. Yasuo Ikeda2,
  21. Akira Hata7,
  22. Shigeru Chiba12,
  23. Keiichi I. Nakayama5, and
  24. Toshio Suda1,6,14
  1. 1 Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582, Japan;
  2. 2 Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan;
  3. 3 PRESTO, Japan Science Technology Agency (JST), Saitama 322-0012, Japan;
  4. 4 Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
  5. 5 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
  6. 6 CREST, Japan Science Technology Agency (JST), Saitama 322-0012, Japan;
  7. 7 Department of Cellular and Molecular Medicine, Chiba University, Chiba 260-8670, Japan;
  8. 8 Department of Public Health, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
  9. 9 Department of Hematology/Oncology, Gunma Children’s Medical Center, Gunma 377-8577, Japan;
  10. 10 Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan;
  11. 11 Department of Developmental Biology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan;
  12. 12 Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo 113-8655, Japan

Abstract

Common molecular machineries between hematopoietic stem cell (HSC) maintenance and leukemia prevention have been highlighted. The tumor suppressor Fbxw7 (F-box and WD-40 domain protein 7), a subunit of an SCF-type ubiquitin ligase complex, induces the degradation of positive regulators of the cell cycle. We demonstrate that inactivation of Fbxw7 in hematopoietic cells causes premature depletion of HSCs due to active cell cycling and p53-dependent apoptosis. Interestingly, Fbxw7 deletion also confers a selective advantage to cells with suppressed p53 function, eventually leading to development of T-cell acute lymphoblastic leukemia (T-ALL). Thus, Fbxw7 functions as a fail-safe mechanism against both premature HSC loss and leukemogenesis.

Keywords

Footnotes

  • ↵13 Corresponding authors.

    ↵13 E-MAIL oike{at}gpo.kumamoto-u.ac.jp; FAX 81-96-373-5145.

  • ↵14 E-MAIL sudato{at}sc.itc.keio.ac.jp; FAX 81-3-5363-3474.

  • Supplemental material is available at http://www.genesdev.org.

  • Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1621808.

    • Received October 1, 2007.
    • Accepted February 22, 2008.

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  1. Published in Advance March 26, 2008, doi: 10.1101/gad.1621808 Genes & Dev. 22: 986-991 Copyright © 2008, Cold Spring Harbor Laboratory Press

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