Crbn I391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice
| Autor: | Tanya Svinkina, James A. Kennedy, Emma C. Fink, D. R. Mani, Benjamin L. Ebert, Dylan N. Adams, Steven A. Carr, Saurav D. Haldar, Michelle C. Chen, Andrew A Guirguis, Namrata D. Udeshi, Brian J. Liddicoat, Marie McConkey, Andrew T. Nguyen |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
biology Chemistry Cereblon Immunology Cell Biology Hematology medicine.disease Pomalidomide Biochemistry IKZF3 Ubiquitin ligase Thalidomide 03 medical and health sciences 030104 developmental biology In vivo medicine biology.protein Cancer research Multiple myeloma Lenalidomide medicine.drug |
| Zdroj: | Blood. 132:1535-1544 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2018-05-852798 |
| Popis: | Thalidomide and its derivatives, lenalidomide and pomalidomide, are clinically effective treatments for multiple myeloma and myelodysplastic syndrome with del(5q). These molecules lack activity in murine models, limiting investigation of their therapeutic activity or toxicity in vivo. Here, we report the development of a mouse model that is sensitive to thalidomide derivatives because of a single amino acid change in the direct target of thalidomide derivatives, cereblon (Crbn). In human cells, thalidomide and its analogs bind CRBN and recruit protein targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and subsequent degradation by the proteasome. We show that mice with a single I391V amino acid change in Crbn exhibit thalidomide-induced degradation of drug targets previously identified in human cells, including Ikaros (Ikzf1), Aiolos (Ikzf3), Zfp91, and casein kinase 1a1 (Ck1α), both in vitro and in vivo. We use the CrbnI391V model to demonstrate that the in vivo therapeutic activity of lenalidomide in del(5q) myelodysplastic syndrome can be explained by heterozygous expression of Ck1α in del(5q) cells. We found that lenalidomide acts on hematopoietic stem cells with heterozygous expression of Ck1α and inactivation of Trp53 causes lenalidomide resistance. We further demonstrate that CrbnI391V is sufficient to confer thalidomide-induced fetal loss in mice, capturing a major toxicity of this class of drugs. Further study of the CrbnI391V model will provide valuable insights into the in vivo efficacy and toxicity of this class of drugs. |
| Databáze: | OpenAIRE |
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