First Author | Rodriguez S | Year | 2020 |
Journal | Leukemia | Volume | 34 |
Issue | 5 | Pages | 1241-1252 |
PubMed ID | 31772299 | Mgi Jnum | J:288478 |
Mgi Id | MGI:6416182 | Doi | 10.1038/s41375-019-0653-z |
Citation | Rodriguez S, et al. (2020) Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL. Leukemia 34(5):1241-1252 |
abstractText | 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). |