bioRxiv preprint doi: https://doi.org/10.1101/619312; this version posted April 25, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Genome-wide CRISPR Screens Reveal Genetic Mediators of Cereblon Modulator Toxicity in Primary Effusion Lymphoma Ajinkya Patil1, Mark Manzano1, and Eva Gottwein1 1Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611 USA. Short Title: Cereblon Modulator Resistance Screens in PEL Corresponding Author: Eva Gottwein Department of Microbiology-Immunology Northwestern University Feinberg School of Medicine 320 E Superior St., Tarry Bldg., Room 6-735 Chicago, Illinois 60611 USA e-mail address:
[email protected] Phone: +1-312-503-3075 Fax: +1-312-503-5101 Word Count Text: 3986 Word Count Abstract: 250 Figure Count: 7 main figures, 8 supplementary figures Table Count: 0 main manuscript, 8 supplementary tables Reference Count: 43 Scientific Category: Lymphoid Neoplasia 1 bioRxiv preprint doi: https://doi.org/10.1101/619312; this version posted April 25, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Genome-wide CRISPR/Cas9 screens represent a powerful approach to study mechanisms of drug action and resistance. Cereblon modulating agents (CMs) have recently emerged as candidates for therapeutic intervention in primary effusion lymphoma (PEL), a highly aggressive cancer caused by Kaposi’s sarcoma-associated herpesvirus. CMs bind to cereblon (CRBN), the substrate receptor of the cullin-RING type E3 ubiquitin ligase CRL4CRBN, and thereby trigger the acquisition and proteasomal degradation of neosubstrates.