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Blood DOI:10.1182/blood-2018-05-852798

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

Publication TypeJournal Article
Year of Publication2018
AuthorsFink, 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
JournalBlood
Volume132
Issue14
Pages1535-1544
Date Published2018 10 04
ISSN1528-0020
KeywordsAdaptor Proteins, Signal Transducing, Animals, Antineoplastic Agents, Casein Kinase I, Disease Models, Animal, Female, Hematopoiesis, Lenalidomide, Male, Mice, Mice, Inbred C57BL, Myelodysplastic Syndromes, Nerve Tissue Proteins, Point Mutation, Thalidomide
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.

DOI10.1182/blood-2018-05-852798
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/30064974?dopt=Abstract

Alternate JournalBlood
PubMed ID30064974
PubMed Central IDPMC6172563
Grant ListF30 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