Browsing by Author "Bonfim-Silva, Ricardo"

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    Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL
    (Springer Nature, 2019-11-26) Rodriguez, Sonia; Abundis, Christina; Boccalatte, Francesco; Mehrotra, Purvi; Chiang, Mark Y.; Yui, Mary A.; Wang, Lin; Zhang, Huajia; Zollman, Amy; Bonfim-Silva, Ricardo; Kloetgen, Andreas; Palmer, Joycelynne; Sandusky, George; Wunderlich, Mark; Kaplan, Mark H.; Mulloy, James C.; Marcucci, Guido; Aifantis, Iannis; Cardoso, Angelo A.; Carlesso, Nadia; Medicine, School of Medicine
    Timed degradation of the cyclin-dependent kinase inhibitor p27Kip1 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/p27Kip1 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).