A genome-scale CRISPR-Cas9 screening in myeloma cells identifies regulators of immunomodulatory drug sensitivity.

Abstract

Immunomodulatory drugs (IMiDs) including lenalidomide and pomalidomide bind cereblon (CRBN) and activate the CRL4CRBN ubiquitin ligase to trigger proteasomal degradation of the essential transcription factors IKZF1 and IKZF3 and multiple myeloma (MM) cytotoxicity. We have shown that CRBN is also targeted for degradation by SCFFbxo7 ubiquitin ligase. In the current study, we explored the mechanisms underlying sensitivity of MM cells to IMiDs using genome-wide CRISPR-Cas9 screening. We validate that CSN9 signalosome complex, a deactivator of Cullin-RING ubiquitin ligase, inhibits SCFFbxo7 E3 ligase-mediated CRBN degradation, thereby conferring sensitivity to IMiDs; conversely, loss of function of CSN9 signalosome activates SCFFbxo7 complex, thereby enhancing degradation of CRBN and conferring IMiD resistance. Finally, we show that pretreatment with either proteasome inhibitors or NEDD8 activating enzyme (NAE) inhibitors can abrogate degradation and maintain levels of CRBN, thereby enhancing sensitivity to IMiDs. These studies therefore demonstrate that CSN9 signalosome complex regulates sensitivity to IMiDs by modulating CRBN expression.

• Authors: Jiye Liu, Tianyu Song, Wenrong Zhou, Lijie Xing, Su Wang, Matthew Ho, Zhengang Peng, Yu-Tzu Tai, Teru Hideshima, Kenneth C Anderson, Yong Cang
• Journal: Leukemia (Leukemia) Vol. 33 Issue 1 Pg. 171-180 (01 2019) ISSN: 1476-5551 [Electronic] England
• PMID: 30026574 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Biomarkers, Tumor
• CRBN protein, human
• Cyclopentanes
• Enzyme Inhibitors
• IKZF3 protein, human
• Immunologic Factors
• Pyrimidines
• Ikaros Transcription Factor
• Bortezomib
• Ubiquitin-Protein Ligases
• Peptide Hydrolases
• COP9 Signalosome Complex
• pevonedistat

Topics

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (genetics, metabolism)
• Bortezomib (pharmacology)
• COP9 Signalosome Complex (antagonists & inhibitors, genetics, metabolism)
• CRISPR-Cas Systems
• Cyclopentanes (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic
• Humans
• Ikaros Transcription Factor (genetics, metabolism)
• Immunologic Factors (pharmacology)
• Multiple Myeloma (drug therapy, genetics, pathology)
• Peptide Hydrolases (genetics, metabolism)
• Prognosis
• Proteolysis
• Pyrimidines (pharmacology)
• Tumor Cells, Cultured
• Ubiquitin-Protein Ligases
• Ubiquitination