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Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells
Rob S. Sellar, … , Chun-Wei Chen, Benjamin L. Ebert
Rob S. Sellar, … , Chun-Wei Chen, Benjamin L. Ebert
Published June 28, 2022
Citation Information: J Clin Invest. 2022;132(16):e153514. https://doi.org/10.1172/JCI153514.
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Research Article Hematology Article has an altmetric score of 40

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

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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.

Authors

Rob S. Sellar, Adam S. Sperling, Mikołaj Słabicki, Jessica A. Gasser, Marie E. McConkey, Katherine A. Donovan, Nada Mageed, Dylan N. Adams, Charles Zou, Peter G. Miller, Ravi K. Dutta, Steffen Boettcher, Amy E. Lin, Brittany Sandoval, Vanessa A. Quevedo Barrios, Veronica Kovalcik, Jonas Koeppel, Elizabeth K. Henderson, Emma C. Fink, Lu Yang, Anthony Chan, Sheela Pangeni Pokharel, Erik J. Bergstrom, Rajan Burt, Namrata D. Udeshi, Steven A. Carr, Eric S. Fischer, Chun-Wei Chen, Benjamin L. Ebert

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Figure 3

CRISPR screens identify the cullin-RING ligase machinery required for CC-885–dependent CRL4CRBN activity and mechanisms of resistance to CC-885.

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CRISPR screens identify the cullin-RING ligase machinery required for CC...
(A) Targeted CRISPR resistance screen showing relative fold enrichment (x axis) of sgRNAs in HEK293T cells treated with 1 μM CC-885 relative to DMSO. (B) Schematic of molecular machinery required for CC-885–induced degradation of GSPT1. (C) Result of genome-wide CRISPR screen showing sgRNAs conferring relative resistance to CC-885 treatment. (D) Selected sgRNAs from arrayed validation screen in MM.1S cells showing fold change in representation following 4 days of treatment with 0.001 μM CC-885. (E) Fold change in sgRNA representation in K562 cells 4 days after treatment with CC-885 at indicated doses. Data points represent combined change in RFP657+ cells for 4 sgRNAs per gene target performed in triplicate ± SEM. NTG, nontargeting guide.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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