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Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2022 , DOI: 10.1172/jci153514
Rob S Sellar 1, 2, 3 , Adam S Sperling 2, 3, 4 , Mikołaj Słabicki 2, 3 , Jessica A Gasser 2, 3 , Marie E McConkey 2, 3 , Katherine A Donovan 5, 6 , Nada Mageed 5, 6 , Dylan N Adams 2 , Charles Zou 2 , Peter G Miller 2, 3 , Ravi K Dutta 4 , Steffen Boettcher 2, 7 , Amy E Lin 2, 3, 8 , Brittany Sandoval 2 , Vanessa A Quevedo Barrios 4 , Veronica Kovalcik 2 , Jonas Koeppel 2, 3 , Elizabeth K Henderson 1 , Emma C Fink 2, 3 , Lu Yang 9 , Anthony Chan 9 , Sheela Pangeni Pokharel 9 , Erik J Bergstrom 3 , Rajan Burt 3 , Namrata D Udeshi 3 , Steven A Carr 3 , Eric S Fischer 5, 6 , Chun-Wei Chen 9 , Benjamin L Ebert 2, 3, 10
Affiliation  

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.

中文翻译:

GSPT1 的降解导致白血病中 TP53 非依赖性细胞死亡,同时保留正常的造血干细胞

靶向蛋白质降解是一种快速发展和扩展的治疗方法。通过 CRL4 CRBN泛素连接酶降解 GSPT1 的药物是积极临床开发中的一类新型癌症疗法,在早期试验中有抗急性髓性白血病活性的证据。然而,除了激活综合应激反应外,导致细胞死亡的 GSPT1 降解的下游效应在很大程度上是不确定的,并且没有可用于研究这些药物的小鼠模型。我们确定了细胞存活所必需的 GSPT1 结构域,并表明 GSPT1 降解会导致翻译终止受损、综合应激反应通​​路激活和TP53-独立的细胞死亡。CRISPR/Cas9 筛选表明,在 GSPT1 降解后,翻译起始减少具有保护作用,这表明翻译水平较高的细胞更容易受到 GSPT1 降解的影响。我们定义了 2 个可防止小鼠 Gspt1 降解的 Crbn 氨基酸,生成了具有这些残基改变的敲入小鼠,并证明了 GSPT1 降解药物在体内的疗效,同时长期造血干细胞的数量和功能相对较少。我们的结果为使用 GSPT1 降解剂治疗癌症(包括TP53突变型急性髓性白血病)提供了机制基础。
更新日期:2022-08-16
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