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Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma

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Item Type:Article
Title:Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma
Creators Name:Bohl, S.R. and Schmalbrock, L.K. and Bauhuf, I. and Meyer, T. and Dolnik, A. and Szyska, M. and Blätte, T.J. and Knödler, S. and Röhner, L. and Miller, D. and Kull, M. and Langer, C. and Döhner, H. and Letai, A. and Damm, F. and Heckl, D. and Bullinger, L. and Krönke, J.
Abstract:The introduction of new drugs in the past years has substantially improved outcome in multiple myeloma (MM). However, the majority of patients eventually relapse and become resistant to one or multiple drugs. While the genetic landscape of relapsed/ resistant multiple myeloma has been elucidated, the causal relationship between relapse-specific gene mutations and the sensitivity to a given drug in MM has not systematically been evaluated. To determine the functional impact of gene mutations, we performed combined whole-exome sequencing (WES) of longitudinal patient samples with CRISPR-Cas9 drug resistance screens for lenalidomide, bortezomib, dexamethasone, and melphalan. WES of longitudinal samples from 16 MM patients identified a large number of mutations in each patient that were newly acquired or evolved from a small subclone (median 9, range 1-55), including recurrent mutations in TP53, DNAH5, and WSCD2. Focused CRISPR-Cas9 resistance screens against 170 relapse-specific mutations functionally linked 15 of them to drug resistance. These included cereblon E3 ligase complex members for lenalidomide, structural genes PCDHA5 and ANKMY2 for dexamethasone, RB1 and CDK2NC for bortezomib, and TP53 for melphalan. In contrast, inactivation of genes involved in the DNA damage repair pathway, including ATM, FANCA, RAD54B, and BRCC3, enhanced susceptibility to cytotoxic chemotherapy. Resistance patterns were highly drug specific with low overlap and highly correlated with the treatment-dependent clonal evolution in patients. The functional association of specific genetic alterations with drug sensitivity will help to personalize treatment of MM in the future.
Keywords:Bortezomib, CRISPR-Cas9, Dexamethasone, Genes, Genetics, Lenalidomide, Lymphoid Neoplasia, Melphalan, Multiple Myeloma, Mutation, Ubiquitin-Protein Ligases
Source:Blood Advances
Publisher:American Society of Hematology
Page Range:2391-2402
Date:11 May 2021
Official Publication:https://doi.org/10.1182/bloodadvances.2020003541
PubMed:View item in PubMed

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