Generation of a lenalidomide-sensitive syngeneic murine in vivo multiple myeloma model by expression of Crbn
| Autor: | Linda Röhner, Andreas Beilhack, Annika Scheffold, Simon Köpff, Stefanie Lindner, Jan Krönke, Yuen Lam Dora Ng, Andreas Brandl |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Cell Survival Ubiquitin-Protein Ligases 03 medical and health sciences Mice 0302 clinical medicine In vivo Cell Line Tumor Genetics medicine Animals Humans Immunologic Factors Point Mutation Molecular Biology Lenalidomide Multiple myeloma Adaptor Proteins Signal Transducing Mice Inbred BALB C Chemistry Cereblon Cell Biology Hematology Pomalidomide medicine.disease IKZF3 Thalidomide Transplantation 030104 developmental biology HEK293 Cells 030220 oncology & carcinogenesis Proteolysis Cancer research Female Multiple Myeloma medicine.drug |
| Zdroj: | Experimental hematology. 93 |
| ISSN: | 1873-2399 |
| Popis: | The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide are approved drugs for the treatment of multiple myeloma. IMiDs induce cereblon (CRBN) E3 ubiquitin ligase-mediated ubiquitination and degradation of Ikaros transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are essential for multiple myeloma. However, because of a single amino acid substitution of valine to isoleucine in mouse CRBN at position 391, mice are not susceptible to IMiD-induced degradation of neosubstrates. Here, we report that expression of human CRBN or the CrbnI391V mutant enables IMiD-induced degradation of IKZF1 and IKZF3 in murine MOPC.315.BM.Luc.eGFP and 5T33MM multiple myeloma cells. Accordingly, lenalidomide and pomalidomide decreased cell viability in a dose-dependent fashion in murine multiple myeloma cells expressing CrbnI391V in vitro. The sensitivity of murine cells expressing CrbnI391V to IMiDs highly correlated with their dependence on IKZF1. After transplantation, MOPC.315.BM.Luc.eGFP cells expressing murine CrbnI391V induced multiple myeloma in mice, and treatment with lenalidomide and pomalidomide significantly delayed tumor growth. This straightforward model provides a proof-of-concept for studying the effects of IMiDs in multiple myeloma in mice, which allows for in vivo testing of IMiDs and other CRBN E3 ligase modulators. |
| Databáze: | OpenAIRE |
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