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Blood. 2018 Oct 4;132(14):1535-1544. doi: 10.1182/blood-2018-05-852798. Epub 2018 Jul 31.

Crbn I391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice.

Fink EC1,2,3, McConkey M1,2,3, Adams DN1,2,3, Haldar SD1,2,3, Kennedy JA1,2,3,4, Guirguis AA1,2,3, Udeshi ND5, Mani DR5, Chen M1,2,3, Liddicoat B1,2,3, Svinkina T5, Nguyen AT1,2,3, Carr SA5, Ebert BL1,2,3.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
2
Department of Hematology, Division of Medicine, Brigham and Women's Hospital, Boston, MA.
3
Cancer Program, Broad Institute, Cambridge, MA.
4
Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada; and.
5
Proteomics Platform, Broad Institute, Cambridge, MA.

Abstract

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 Crbn I391V 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 Crbn I391V is sufficient to confer thalidomide-induced fetal loss in mice, capturing a major toxicity of this class of drugs. Further study of the Crbn I391V model will provide valuable insights into the in vivo efficacy and toxicity of this class of drugs.

PMID:
30064974
PMCID:
PMC6172563
DOI:
10.1182/blood-2018-05-852798
[Indexed for MEDLINE]
Free PMC Article

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