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

Sahoko Matsuoka, Yuichi Oike, Ichiro Onoyama, Atsushi Iwama, Fumio Arai, Keiyo Takubo, Yoichi Mashimo, Hideyuki Oguro, Eriko Nitta, Keisuke Ito, Kana Miyamoto, Hiroki Yoshiwara, Kentaro Hosokawa, Yuka Nakamura, Yumiko Gomei, Hiroko Iwasaki, Yasuhide Hayashi, Yumi Matsuzaki, Keiko Nakayama, Yasuo IkedaAkira Hata, Shigeru Chiba, Keiichi I. Nakayama, Toshio Suda

Research output: Contribution to journalArticle

129 Citations (Scopus)

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 (TALL). Thus, Fbxw7 functions as a fail-safe mechanism against both premature HSC loss and leukemogenesis.

Original languageEnglish
Pages (from-to)986-991
Number of pages6
JournalGenes and Development
Volume22
Issue number8
DOIs
Publication statusPublished - Apr 15 2008

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

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    Matsuoka, S., Oike, Y., Onoyama, I., Iwama, A., Arai, F., Takubo, K., Mashimo, Y., Oguro, H., Nitta, E., Ito, K., Miyamoto, K., Yoshiwara, H., Hosokawa, K., Nakamura, Y., Gomei, Y., Iwasaki, H., Hayashi, Y., Matsuzaki, Y., Nakayama, K., ... Suda, T. (2008). Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL. Genes and Development, 22(8), 986-991. https://doi.org/10.1101/gad.1621808