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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:132 |
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| Enthalten in: |
The Journal of clinical investigation - 132(2022), 16 vom: 15. Aug. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sellar, Rob S [VerfasserIn] |
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| Links: |
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| Themen: |
Hematology |
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| Anmerkungen: |
Date Completed 16.08.2022 Date Revised 10.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1172/JCI153514 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM342843052 |
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| 100 | 1 | |a Sellar, Rob S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells |
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| 500 | |a Date Completed 16.08.2022 | ||
| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Hematology | |
| 650 | 4 | |a Leukemias | |
| 650 | 4 | |a Mouse models | |
| 650 | 4 | |a Therapeutics | |
| 650 | 4 | |a Ubiquitin-proteosome system | |
| 650 | 7 | |a Peptide Termination Factors |2 NLM | |
| 700 | 1 | |a Sperling, Adam S |e verfasserin |4 aut | |
| 700 | 1 | |a Słabicki, Mikołaj |e verfasserin |4 aut | |
| 700 | 1 | |a Gasser, Jessica A |e verfasserin |4 aut | |
| 700 | 1 | |a McConkey, Marie E |e verfasserin |4 aut | |
| 700 | 1 | |a Donovan, Katherine A |e verfasserin |4 aut | |
| 700 | 1 | |a Mageed, Nada |e verfasserin |4 aut | |
| 700 | 1 | |a Adams, Dylan N |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Charles |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Peter G |e verfasserin |4 aut | |
| 700 | 1 | |a Dutta, Ravi K |e verfasserin |4 aut | |
| 700 | 1 | |a Boettcher, Steffen |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Amy E |e verfasserin |4 aut | |
| 700 | 1 | |a Sandoval, Brittany |e verfasserin |4 aut | |
| 700 | 1 | |a Quevedo Barrios, Vanessa A |e verfasserin |4 aut | |
| 700 | 1 | |a Kovalcik, Veronica |e verfasserin |4 aut | |
| 700 | 1 | |a Koeppel, Jonas |e verfasserin |4 aut | |
| 700 | 1 | |a Henderson, Elizabeth K |e verfasserin |4 aut | |
| 700 | 1 | |a Fink, Emma C |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Anthony |e verfasserin |4 aut | |
| 700 | 1 | |a Pokharel, Sheela Pangeni |e verfasserin |4 aut | |
| 700 | 1 | |a Bergstrom, Erik J |e verfasserin |4 aut | |
| 700 | 1 | |a Burt, Rajan |e verfasserin |4 aut | |
| 700 | 1 | |a Udeshi, Namrata D |e verfasserin |4 aut | |
| 700 | 1 | |a Carr, Steven A |e verfasserin |4 aut | |
| 700 | 1 | |a Fischer, Eric S |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Chun-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Ebert, Benjamin L |e verfasserin |4 aut | |
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