标题:A genome-scale CRISPR-Cas9 screening in myeloma cells identifies regulators of immunomodulatory drug sensitivity
作者:Liu, Jiye; Song, Tianyu; Zhou, Wenrong; Xing, Lijie; Wang, Su; Ho, Matthew; Peng, Zhengang; Tai, Yu-Tzu; Hideshima, Teru; Anderson, 更多
作者机构:[Liu, Jiye; Xing, Lijie; Ho, Matthew; Tai, Yu-Tzu; Hideshima, Teru; Anderson, Kenneth C.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Jero 更多
通讯作者:Anderson, KC;Cang, Y
通讯作者地址:[Anderson, KC]Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA;[Cang, Y]ShanghaiTech U 更多
来源:LEUKEMIA
出版年:2019
卷:33
期:1
页码:171-180
DOI:10.1038/s41375-018-0205-y
摘要:Immunomodulatory drugs (IMiDs) including lenalidomide and pomalidomide bind cereblon (CRBN) and activate the CRL4(C)(RBN) 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.
收录类别:SCOPUS;SCIE
Scopus被引频次:2
资源类型:期刊论文
原文链接:https://www.scopus.com/inward/record.uri?eid=2-s2.0-85050287355&doi=10.1038%2fs41375-018-0205-y&partnerID=40&md5=5774423d607a0c07e130a3c8b8689656
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