Matsuoka Sahoko, Oike Yuichi, Onoyama Ichiro, Iwama Atsushi, Arai Fumio, Takubo Keiyo, Mashimo Yoichi, Oguro Hideyuki, Nitta Eriko, Ito Keisuke, Miyamoto Kana, Yoshiwara Hiroki, Hosokawa Kentaro, Nakamura Yuka, Gomei Yumiko, Iwasaki Hiroko, Hayashi Yasuhide, Matsuzaki Yumi, Nakayama Keiko, Ikeda Yasuo, Hata Akira, Chiba Shigeru, Nakayama Keiichi I, Suda Toshio
Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Genes Dev. 2008 Apr 15;22(8):986-91. doi: 10.1101/gad.1621808. Epub 2008 Mar 26.
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.
造血干细胞（HSC）维持与白血病预防之间常见的分子机制已得到凸显。肿瘤抑制因子Fbxw7（F-box和WD-40结构域蛋白7）是SCF型泛素连接酶复合物的一个亚基，可诱导细胞周期正调控因子的降解。我们证明，造血细胞中Fbxw7的失活会由于活跃的细胞周期和p53依赖的凋亡导致HSCs过早耗竭。有趣的是，Fbxw7缺失也赋予p53功能受抑制的细胞选择性优势，最终导致T细胞急性淋巴细胞白血病（T-ALL）的发生。因此，Fbxw7作为一种针对过早的HSC损失和白血病发生的故障安全机制发挥作用。
