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

  • Leukemia. 2020 May;34(5):1241-1252. doi: 10.1038/s41375-019-0653-z.
Sonia Rodriguez  1  2 ,  Christina Abundis  1 ,  Francesco Boccalatte  3 ,  Purvi Mehrotra  2 ,  Mark Y Chiang  4 ,  Mary A Yui  5 ,  Lin Wang  2  6 ,  Huajia Zhang  2  7 ,  Amy Zollman  2 ,  Ricardo Bonfim-Silva  2  8 ,  Andreas Kloetgen  3 ,  Joycelynne Palmer  1 ,  George Sandusky  6 ,  Mark Wunderlich  9 ,  Mark H Kaplan  2 ,  James C Mulloy  9 ,  Guido Marcucci  1 ,  Iannis Aifantis  3 ,  Angelo A Cardoso  1 ,  Nadia Carlesso  10  11
Affiliations
  • 1. Beckman Research Institute, Gehr Leukemia Center, City of Hope, Duarte, CA, 91010, USA.
  • 2. Herman B Wells Center, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
  • 3. Department of Pathology and Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, 10016, USA.
  • 4. Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.
  • 5. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
  • 6. Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
  • 7. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
  • 8. Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Riberão Preto, São Paulo, 14049-900, Brazil.
  • 9. Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
  • 10. Beckman Research Institute, Gehr Leukemia Center, City of Hope, Duarte, CA, 91010, USA. [email protected].
  • 11. Herman B Wells Center, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. [email protected].
PMID: 31772299 DOI: 10.1038/s41375-019-0653-z
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).

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