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

Sellar, Rob S; Sperling, Adam S; Słabicki, Mikołaj; Gasser, Jessica A; McConkey, Marie E; Donovan, Katherine A; Mageed, Nada; ... Ebert, Benjamin L; + view all (2022) Degradation of GSPT1 causes TP53-independent cell death in leukemia whilst sparing normal hematopoietic stem cells. The Journal of Clinical Investigation 10.1172/JCI153514. (In press). Green open access

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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 to GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to GSPT1 degradation. We defined two Crbn amino acids that prevent Gspt1 degradation in mice, generated a knock-in 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 AML.

Type: Article
Title: Degradation of GSPT1 causes TP53-independent cell death in leukemia whilst sparing normal hematopoietic stem cells
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/JCI153514
Publisher version: https://doi.org/10.1172/JCI153514
Language: English
Additional information: Copyright © 2022, Sellar et al. 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/.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10153344
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