期刊
LEUKEMIA
卷 34, 期 5, 页码 1241-1252出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41375-019-0653-z
关键词
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资金
- NCI NIH HHS [R01 CA196604, P30 CA033572] Funding Source: Medline
- NIAID NIH HHS [R01 AI136941] Funding Source: Medline
- NIDDK NIH HHS [R01 DK097837, P30 DK090948] Funding Source: Medline
Timed degradation of the cyclin-dependent kinase inhibitor p27(Kip1) by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of T-ALL. Here, we determined that SKP2 function is relevant for T-ALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human T-ALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27(Kip1) pathway plays a unique role in T-ALL development and provide a proof-of-concept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL).
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