SCF^Fbxo7 Ubiquitin Ligase Targets Cereblon To Limit The Anti-myeloma Activity Of IMiDs

Multiple myeloma patients have witnessed significantly improved survival after the approved treatment with the proteasome inhibitor bortezomib and immunomodulatory drugs (IMiDs). IMiDs directly bind cereblon (CRBN), an adaptor of the Cul4-DDB1 (CRL4) ubiquitin ligase, and activate CRL4CRBN to target B cell-specific transcription factors IKZF1 and IKZF3 for ubiquitination. IKZF1 and IKZF3 are essential for MM cell survival and their proteasomal degradation induced by IMiDs provides insights into how these drugs work. Paradoxically, IMiDs achieve better clinical response in MM patients when combined with bortezomib, which blocks IKZF1 and IKZF3 turnover and would in principle counteract with IMiDs. We performed a CRISPR-based genome-wide knockout screening for regulators of pomalidomide sensitivity in MM cells, and found that CRBN is inherently unstable and its level is controlled by the COP9 signalosome (CSN). When unbound to CRL4, CRBN is targeted by SCFfbxo7 ubiquitin ligase for ubiquitination and degradation, a process suppressed by CSN-mediated de-neddylation of Cull. Bortezomib stabilizes CRBN and IMiDs further promote the loading of CRBN to CRL4, leading to enhanced turnover of IKZF1 and IKZF3 in MM cells and synergistic inhibition of MM cell proliferation. This is the first research to explore the reason for which MM resistant to IMiDs. Moreover, Our findings provide a framework to select patients most susceptible to bortezomib and IMiDs combination therapy.