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

Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4(CRBN) 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. Howeve...

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Autores principales: Sellar, Rob S., Sperling, Adam S., Słabicki, Mikołaj, Gasser, Jessica A., McConkey, Marie E., Donovan, Katherine A., Mageed, Nada, Adams, Dylan N., Zou, Charles, Miller, Peter G., Dutta, Ravi K., Boettcher, Steffen, Lin, Amy E., Sandoval, Brittany, Quevedo Barrios, Vanessa A., Kovalcik, Veronica, Koeppel, Jonas, Henderson, Elizabeth K., Fink, Emma C., Yang, Lu, Chan, Anthony, Pokharel, Sheela Pangeni, Bergstrom, Erik J., Burt, Rajan, Udeshi, Namrata D., Carr, Steven A., Fischer, Eric S., Chen, Chun-Wei, Ebert, Benjamin L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9374383/
https://www.ncbi.nlm.nih.gov/pubmed/35763353
http://dx.doi.org/10.1172/JCI153514
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author Sellar, Rob S.
Sperling, Adam S.
Słabicki, Mikołaj
Gasser, Jessica A.
McConkey, Marie E.
Donovan, Katherine A.
Mageed, Nada
Adams, Dylan N.
Zou, Charles
Miller, Peter G.
Dutta, Ravi K.
Boettcher, Steffen
Lin, Amy E.
Sandoval, Brittany
Quevedo Barrios, Vanessa A.
Kovalcik, Veronica
Koeppel, Jonas
Henderson, Elizabeth K.
Fink, Emma C.
Yang, Lu
Chan, Anthony
Pokharel, Sheela Pangeni
Bergstrom, Erik J.
Burt, Rajan
Udeshi, Namrata D.
Carr, Steven A.
Fischer, Eric S.
Chen, Chun-Wei
Ebert, Benjamin L.
author_facet Sellar, Rob S.
Sperling, Adam S.
Słabicki, Mikołaj
Gasser, Jessica A.
McConkey, Marie E.
Donovan, Katherine A.
Mageed, Nada
Adams, Dylan N.
Zou, Charles
Miller, Peter G.
Dutta, Ravi K.
Boettcher, Steffen
Lin, Amy E.
Sandoval, Brittany
Quevedo Barrios, Vanessa A.
Kovalcik, Veronica
Koeppel, Jonas
Henderson, Elizabeth K.
Fink, Emma C.
Yang, Lu
Chan, Anthony
Pokharel, Sheela Pangeni
Bergstrom, Erik J.
Burt, Rajan
Udeshi, Namrata D.
Carr, Steven A.
Fischer, Eric S.
Chen, Chun-Wei
Ebert, Benjamin L.
author_sort Sellar, Rob S.
collection PubMed
description Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4(CRBN) 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.
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spelling pubmed-93743832022-08-18 Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells Sellar, Rob S. Sperling, Adam S. Słabicki, Mikołaj Gasser, Jessica A. McConkey, Marie E. Donovan, Katherine A. Mageed, Nada Adams, Dylan N. Zou, Charles Miller, Peter G. Dutta, Ravi K. Boettcher, Steffen Lin, Amy E. Sandoval, Brittany Quevedo Barrios, Vanessa A. Kovalcik, Veronica Koeppel, Jonas Henderson, Elizabeth K. Fink, Emma C. Yang, Lu Chan, Anthony Pokharel, Sheela Pangeni Bergstrom, Erik J. Burt, Rajan Udeshi, Namrata D. Carr, Steven A. Fischer, Eric S. Chen, Chun-Wei Ebert, Benjamin L. J Clin Invest Research Article Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4(CRBN) 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. American Society for Clinical Investigation 2022-08-15 2022-08-15 /pmc/articles/PMC9374383/ /pubmed/35763353 http://dx.doi.org/10.1172/JCI153514 Text en © 2022 Sellar et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Sellar, Rob S.
Sperling, Adam S.
Słabicki, Mikołaj
Gasser, Jessica A.
McConkey, Marie E.
Donovan, Katherine A.
Mageed, Nada
Adams, Dylan N.
Zou, Charles
Miller, Peter G.
Dutta, Ravi K.
Boettcher, Steffen
Lin, Amy E.
Sandoval, Brittany
Quevedo Barrios, Vanessa A.
Kovalcik, Veronica
Koeppel, Jonas
Henderson, Elizabeth K.
Fink, Emma C.
Yang, Lu
Chan, Anthony
Pokharel, Sheela Pangeni
Bergstrom, Erik J.
Burt, Rajan
Udeshi, Namrata D.
Carr, Steven A.
Fischer, Eric S.
Chen, Chun-Wei
Ebert, Benjamin L.
Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells
title Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells
title_full Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells
title_fullStr Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells
title_full_unstemmed Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells
title_short Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells
title_sort degradation of gspt1 causes tp53-independent cell death in leukemia while sparing normal hematopoietic stem cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9374383/
https://www.ncbi.nlm.nih.gov/pubmed/35763353
http://dx.doi.org/10.1172/JCI153514
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