Gale and Ira Drukier Institute for Children's Health

You are here

Comprehensive characterization of the mutational landscape in multiple myeloma cell lines reveals potential drivers and pathways associated with tumor progression and drug resistance.

TitleComprehensive characterization of the mutational landscape in multiple myeloma cell lines reveals potential drivers and pathways associated with tumor progression and drug resistance.
Publication TypeJournal Article
Year of Publication2019
AuthorsVikova V, Jourdan M, Robert N, Requirand G, Boireau S, Bruyer A, Vincent L, Cartron G, Klein B, Elemento O, Kassambara A, Moreaux J
JournalTheranostics
Volume9
Issue2
Pagination540-553
Date Published2019
ISSN1838-7640
Abstract

Human multiple myeloma tumor cell lines (HMCLs) have been a cornerstone of research in multiple myeloma (MM) and have helped to shape our understanding of molecular processes that drive tumor progression. A comprehensive characterization of genomic mutations in HMCLs will provide a basis for choosing relevant cell line models to study a particular aspect of myeloma biology, or to screen for an antagonist of certain cancer pathways. We performed whole exome sequencing on a large cohort of 30 HMCLs, representative of a large molecular heterogeneity of MM, and 8 control samples (epstein-barr virus (EBV)-immortalized B-cells obtained from 8 different patients). We evaluated the sensitivity of HMCLs to ten drugs. We identified a high confidence list of 236 protein-coding genes with mutations affecting the structure of the encoded protein. Among the most frequently mutated genes, there were known MM drivers, such as , , , and , as well as novel mutated genes, including , , and . We next generated a comprehensive map of altered key pathways in HMCLs. These include cell growth pathways (MAPK, JAK-STAT, PI(3)K-AKT and TP53 / cell cycle pathway), DNA repair pathway and chromatin modifiers. Importantly, our analysis highlighted a significant association between the mutation of several genes and the response to conventional drugs used in MM as well as targeted inhibitors. Taken together, this first comprehensive exome-wide analysis of the mutational landscape in HMCLs provides unique resources for further studies and identifies novel genes potentially associated with MM pathophysiology, some of which may be targets for future therapeutic intervention.

DOI10.7150/thno.28374
Alternate JournalTheranostics
PubMed ID30809292
PubMed Central IDPMC6376179