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Leukemia. 2019 Jan;33(1):171-180. doi: 10.1038/s41375-018-0205-y. Epub 2018 Jul 19.

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

Author information

1
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
2
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
3
Oncology Business Unit and Innovation Center for Cell Signalling Network, WuXi AppTec Group, Shanghai, China.
4
Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
5
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
6
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Kenneth_anderson@dfci.harvard.edu.
7
School of Life Science and Technology, ShanghaiTech University, Shanghai, China. cangyong@shanghaitech.edu.cn.

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.

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