MassIVE MSV000082653

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CrbnI391V is sufficient to confer in vivo sensitivity to thalidomide derivatives in mice

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Description

Fink EC, McConkey M, Adams DN, Haldar SD, Guirguis A, Udeshi ND, Kennedy JA, Mani DR, Chen M, Svinkina T, Nguyen A, Carr SA, and Ebert BL. Blood 2018. Thalidomide, infamous for its teratogenic effects, and derivatives lenalidomide and pomalidomide have found new clinical utility as treatments for multiple myeloma and myelodysplastic syndrome with del(5q). Despite their widespread clinical use, studies of these drugs have been limited by their lack of effect in rodent models. Here, we report the development of a knock-in mouse that is sensitive to thalidomide derivatives. Thalidomide analogs bind to CRBN and recruit protein targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and subsequent degradation by the proteasome. Mice with a single amino acid change in Crbn, CrbnI391V, have thalidomide-induced degradation of drug targets identified in human cells including Ikaros, Aiolos, Zfp91, and Ck1-alpha. Previous work suggested that haploinsufficient expression of Ck1-alpha could explain the efficacy of lenalidomide in del(5q) myelodysplastic syndrome. Using the CrbnI391V model, we demonstrate that haploinsufficiency for Ck1-alpha confers lenalidomide sensitivity in vivo and that both lenalidomide-induced selection and Trp53-mediated resistance occur at the level of hematopoietic stem cells. We also demonstrate that CrbnI391V is sufficient to confer thalidomide-induced fetal loss in mice. Further study of the CrbnI391V model will provide valuable insights into the in vivo efficacy and toxicity of this class of drugs. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: TMT10 ; thalidomide

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Principal Investigators:
(in alphabetical order) 		Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: clauser
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