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

Blood
Authors
Keywords
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 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 in vitro and in vivo. We use the 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 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 in vivo efficacy and toxicity of this class of drugs.

Year of Publication
2018
Journal
Blood
Volume
132
Issue
14
Pages
1535-1544
Date Published
2018 10 04
ISSN
1528-0020
DOI
10.1182/blood-2018-05-852798
PubMed ID
30064974
PubMed Central ID
PMC6172563
Links
Grant list
F30 CA199988 / CA / NCI NIH HHS / United States
P50 CA206963 / CA / NCI NIH HHS / United States
R01 HL082945 / HL / NHLBI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
P01 CA108631 / CA / NCI NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States