|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Fink, EC, McConkey, M, Adams, DN, Haldar, SD, Kennedy, JA, Guirguis, AA, Udeshi, ND, Mani, DR, Chen, M, Liddicoat, B, Svinkina, T, Nguyen, AT, Carr, SA, Ebert, BL|
|Date Published||2018 Jul 31|
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 Here, we report the development of a mouse model that is sensitive to thalidomide derivatives due to a single amino acid change in the direct target of thalidomide derivatives, Crbn. In human cells, thalidomide and its analogs bind CRBN and recruit protein targets to the CRL4 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 and We use the model to demonstrate that the 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 causes lenalidomide resistance. We further demonstrate that is sufficient to confer thalidomide-induced fetal loss in mice, capturing a major toxicity of this class of drugs. Further study of the model will provide valuable insights into the efficacy and toxicity of this class of drugs.