BET Bromodomain Blockade Enhances Ikaros Inhibition By Lenalidomide Therapy Providing Additional Activity in In Vitro and In Vivo Models of Multiple Myeloma (original) (raw)

Blood

Abstract

Introduction: Even with the use of novel drugs in patients with multiple myeloma (MM), relapse remains a challenge. Anti-myeloma activity of the immunomodulatory drug lenalidomide has been shown to rely on cereblon E3 ubiquitin ligase complex-dependent degradation of IRF4 and Ikaros, both required for MM cell survival. As these two factors are involved in the regulation of MYC transcription, we wanted to evaluate the effect of combining a MYC-interfering therapy with a lenalidomide and dexamethasone (Len/Dex) regimen. Methods: Seven MM cell lines (ARP-1, JJN-3, U266, MM.1S, MM.1R, RMPI-8226 and KMM.1) were exposed to the BET bromodomain inhibitor CPI203 in the presence or absence of a standard dose of Len/Dex, followed by MTT assay, flow cytometry, western blot and gene expression arrays. Significant gene signatures were identified using gene set enrichment analysis (GSEA) v2.0 (Broad Institute at MIT). These results were validated in primary cells derived from bone marrow of 9 pati...

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