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

Leukemia
Jiye LiuYong Cang

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.

References

Nov 24, 1999·The New England Journal of Medicine·S SinghalB Barlogie
May 5, 2001·Science·S LyapinaR J Deshaies
Dec 12, 2001·Seminars in Oncology·T HideshimaK C Anderson
May 7, 2002·Nature Reviews. Cancer·W Michael Kuehl, P Leif Bergsagel
Jun 17, 2005·The New England Journal of Medicine·Paul G RichardsonUNKNOWN Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators
Jul 25, 2007·Nature Reviews. Cancer·Teru HideshimaKenneth C Anderson
Apr 11, 2009·Nature·Teresa A SoucySteven P Langston
Sep 2, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Martha Q LacyS Vincent Rajkumar
Mar 13, 2010·Science·Takumi ItoHiroshi Handa
Mar 18, 2011·The New England Journal of Medicine·Antonio Palumbo, Kenneth Anderson
Aug 31, 2011·Cell Cycle·Mong-Hong LeeSai-Ching J Yeung
May 11, 2012·The New England Journal of Medicine·Philip L McCarthyCharles Linker
Jan 5, 2013·Science·Le CongFeng Zhang
Jan 5, 2013·Science·Prashant MaliGeorge M Church
Apr 30, 2013·Oncogene·E K Lee, J A Diehl
May 10, 2013·Nature Reviews. Molecular Cell Biology·Jeffrey R SkaarMichele Pagano
Jun 19, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Thomas M HerndonRichard Pazdur
Dec 18, 2013·Science·Tim WangEric S Lander
Dec 18, 2013·Science·Ophir ShalemFeng Zhang
Jul 22, 2014·Nature·Gondichatnahalli M LingarajuNicolas H Thomä
Jul 22, 2014·Nature·Eric S FischerNicolas H Thomä
Jul 31, 2014·Nature Methods·Neville E SanjanaFeng Zhang
Aug 12, 2014·Nature Structural & Molecular Biology·Philip P ChamberlainBrian E Cathers
Sep 4, 2014·The New England Journal of Medicine·David Avigan, Jacalyn Rosenblatt
Jun 3, 2015·The New England Journal of Medicine·Sagar LonialUNKNOWN ELOQUENT-2 Investigators
Jun 23, 2015·FEBS Letters·Dawadschargal DubielWolfgang Dubiel
Aug 27, 2015·The New England Journal of Medicine·Henk M LokhorstPaul G Richardson
Sep 13, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jacob P LaubachPaul G Richardson
Jan 6, 2016·Drugs·Kate McKeage
Feb 6, 2016·Drugs·Matt Shirley
Apr 6, 2017·The New England Journal of Medicine·Michel AttalUNKNOWN IFM 2009 Study
Dec 3, 2017·Cancer Metastasis Reviews·Sara GandolfiPaul G Richardson

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Citations

Apr 14, 2019·Journal of Experimental & Clinical Cancer Research : CR·Qian LiangZhizheng Ge
Aug 8, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Francesco MauraGareth J Morgan
Dec 27, 2019·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Linzhi YanXueqiong Zhu
Oct 30, 2020·Frontiers in Immunology·Mohammadreza Azangou-KhyavyJafar Kiani
Nov 13, 2020·Pharmacological Reviews·Samir H Barghout, Aaron D Schimmer
Jan 25, 2020·Molecular Cell·Kurt M ReichermeierDonald S Kirkpatrick
Jun 17, 2019·Pharmacology & Therapeutics·Tomoko Asatsuma-OkumuraHiroshi Handa
Apr 4, 2021·Cell Chemical Biology·Natalie S ScholesGeorg E Winter
Jun 7, 2021·Biomarker Research·Shichao WangShaobing Gao
Jul 1, 2021·Clinical & Translational Immunology·Lukman O AfolabiXiaochun Wan
Sep 30, 2021·Proceedings of the National Academy of Sciences of the United States of America·Thang Van Nguyen

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Methods Mentioned

BETA
ubiquitination
transfection
PCR
immunoprecipitation
Assay
neddylation

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