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

Theranostics
Veronika VikovaJérôme Moreaux

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. Methods: 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. Results: 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 TP53, KRAS, NRAS, ATM and FAM46C, as well as novel mutated genes, including CNOT3, KMT2D, MSH3 and PMS1. 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 ...Continue Reading

Citations

Jul 23, 2019·Expert Opinion on Emerging Drugs·Judith LindKlaus Podar
Nov 1, 2020·International Journal of Molecular Sciences·Emmanuel VarletJerome Moreaux
Nov 5, 2020·Wiley Interdisciplinary Reviews. RNA·Vladyslava Liudkovska, Andrzej Dziembowski
Jul 30, 2021·Journal of Immunological Methods·Marileen M C PrinsManon E Wildenberg
Dec 19, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ying JinMing Chen

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Datasets Mentioned

BETA
E-TABM-937

Methods Mentioned

BETA
exome sequencing

Software Mentioned

GATK
maftools R package
Bowtie 2 aligner
R
SIFT
ANNOVAR
FATHMM
FactoMineR
factoextra
BCFtools

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