Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL.
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.
Matsuoka
Sahoko
S
Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Oike
Yuichi
Y
Onoyama
Ichiro
I
Iwama
Atsushi
A
Arai
Fumio
F
Takubo
Keiyo
K
Mashimo
Yoichi
Y
Oguro
Hideyuki
H
Nitta
Eriko
E
Ito
Keisuke
K
Miyamoto
Kana
K
Yoshiwara
Hiroki
H
Hosokawa
Kentaro
K
Nakamura
Yuka
Y
Gomei
Yumiko
Y
Iwasaki
Hiroko
H
Hayashi
Yasuhide
Y
Matsuzaki
Yumi
Y
Nakayama
Keiko
K
Ikeda
Yasuo
Y
Hata
Akira
A
Chiba
Shigeru
S
Nakayama
Keiichi I
KI
Suda
Toshio
T
D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases