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  3. Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells

Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells

  • J Clin Invest. 2022 Aug 15;132(16):e153514. doi: 10.1172/JCI153514.
Rob S Sellar 1 2 3,  Adam S Sperling 2 3 4,  Mikołaj Słabicki 2 3,  Jessica A Gasser 2 3,  Marie E McConkey 2 3,  Katherine A Donovan 5 6,  Nada Mageed 5 6,  Dylan N Adams 2,  Charles Zou 2,  Peter G Miller 2 3,  Ravi K Dutta 4,  Steffen Boettcher 2 7,  Amy E Lin 2 3 8,  Brittany Sandoval 2,  Vanessa A Quevedo Barrios 4,  Veronica Kovalcik 2,  Jonas Koeppel 2 3,  Elizabeth K Henderson 1,  Emma C Fink 2 3,  Lu Yang 9,  Anthony Chan 9,  Sheela Pangeni Pokharel 9,  Erik J Bergstrom 3,  Rajan Burt 3,  Namrata D Udeshi 3,  Steven A Carr 3,  Eric S Fischer 5 6,  Chun-Wei Chen 9,  Benjamin L Ebert 2 3 10
Affiliations

Affiliations

  • 1 Department of Haematology, UCL Cancer Institute, University College London, London, United Kingdom.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 3 Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • 4 Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
  • 7 Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
  • 8 Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • 9 Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
  • 10 Howard Hughes Medical Institute, Boston, Massachusetts, USA.
PMID: 35763353 DOI: 10.1172/JCI153514
Abstract

Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are a new class of Cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early-phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation leading to cell death are largely undefined, and no murine models are available to study these agents. We identified the domains of GSPT1 essential for cell survival and show that GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response pathway, and TP53-independent cell death. CRISPR/Cas9 screens implicated decreased translation initiation as protective following GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to the effects of GSPT1 degradation. We defined 2 Crbn Amino acids that prevent Gspt1 degradation in mice, generated a knockin mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of Cancer, including TP53-mutant acute myeloid leukemia.

Keywords

Hematology; Leukemias; Mouse models; Therapeutics; Ubiquitin-proteosome system.

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