Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL

Sonia Rodriguez, Christina Abundis, Francesco Boccalatte, Purvi Mehrotra, Mark Y. Chiang, Mary A. Yui, Lin Wang, Huajia Zhang, Amy Zollman, Ricardo Bonfim-Silva, Andreas Kloetgen, Joycelynne Palmer, George Sandusky, Mark Wunderlich, Mark H. Kaplan, James C. Mulloy, Guido Marcucci, Iannis Aifantis, Angelo A. Cardoso, Nadia Carlesso

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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).

Original languageEnglish (US)
Pages (from-to)1241-1252
Number of pages12
JournalLeukemia
Volume34
Issue number5
DOIs
StatePublished - May 1 2020

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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