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

Autor:	Sellar RS; Department of Haematology, UCL Cancer Institute, University College London, London, United Kingdom.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Sperling AS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA., Słabicki M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Gasser JA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., McConkey ME; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Donovan KA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Mageed N; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Adams DN; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Zou C; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Miller PG; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Dutta RK; Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA., Boettcher S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland., Lin AE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA., Sandoval B; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Quevedo Barrios VA; Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA., Kovalcik V; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Koeppel J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Henderson EK; Department of Haematology, UCL Cancer Institute, University College London, London, United Kingdom., Fink EC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Yang L; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, California, USA., Chan A; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, California, USA., Pokharel SP; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, California, USA., Bergstrom EJ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Burt R; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Udeshi ND; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Carr SA; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Fischer ES; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Chen CW; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, California, USA., Ebert BL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Howard Hughes Medical Institute, Boston, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2022 Aug 15; Vol. 132 (16).
DOI:	10.1172/JCI153514
Abstrakt:	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.
Databáze:	MEDLINE
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