Whole-exon sequencing of human myeloma cell lines shows mutations related to myeloma patients at relapse with major hits in the DNA regulation and repair pathways

• Published in: Journal of hematology and oncology Vol. 11; no. 1; pp. 137 - 13
• Main Authors: Tessoulin, Benoît, Moreau-Aubry, Agnès, Descamps, Géraldine, Gomez-Bougie, Patricia, Maïga, Sophie, Gaignard, Alban, Chiron, David, Ménoret, Emmanuelle, Le Gouill, Steven, Moreau, Philippe, Amiot, Martine, Pellat-Deceunynck, Catherine
• Format: Journal Article
• Language: English
• Published: London BioMed Central 13.12.2018; BioMed Central Ltd; BMC
• Subjects: Apoptosis; Breast cancer; Cancer; Cancer Research; Cell cycle; Cell Line; Chromatin; Clonal deletion; Cyclin-dependent kinases; Deoxyribonucleic acid; DNA; DNA - genetics; DNA repair; DNA Repair - genetics; DNA sequencing; Drug screening; Exons; Fanconi pathway; Fanconi syndrome; Gene deletion; Gene expression; Genetic aspects; Genetic testing; Genomes; Genomics; Hematology; Humans; Kinases; Leukemia; Life Sciences; Lymphoma; MAP kinase; Measles; Medicine; Medicine & Public Health; Missense mutation; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Mutation; Myeloma; Myelomas; NF-κB protein; Nucleotide sequencing; Oncology; p53 Protein; Patients; Physiological aspects; Point mutation; RNA polymerase; Tumor cell lines; Tumor suppressor genes; Tumor Suppressor Protein p53 - metabolism; Tumor suppressors; WES; France; Myelomas; WES; Tumor suppressors; DNA repair; Fanconi pathway
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-018-0679-0

Background Human myeloma cell lines (HMCLs) are widely used for their representation of primary myeloma cells because they cover patient diversity, although not fully. Their genetic background is mostly undiscovered, and no comprehensive study has ever been conducted in order to reveal those details. Methods We performed whole-exon sequencing of 33 HMCLs, which were established over the last 50 years in 12 laboratories. Gene expression profiling and drug testing for the 33 HMCLs are also provided and correlated to exon-sequencing findings. Results Missense mutations were the most frequent hits in genes (92%). HMCLs harbored between 307 and 916 mutations per sample, with TP53 being the most mutated gene (67%). Recurrent bi-allelic losses were found in genes involved in cell cycle regulation ( RB1 , CDKN2C ), the NFκB pathway ( TRAF3 , BIRC2 ), and the p53 pathway ( TP53 , CDKN2A ). Frequency of mutations/deletions in HMCLs were either similar to that of patients (e.g., DIS3 , PRDM1 , KRAS) or highly increased (e.g., TP53 , CDKN2C , NRAS , PRKD2) . MAPK was the most altered pathway (82% of HMCLs), mainly by RAS mutants. Surprisingly, HMCLs displayed alterations in epigenetic (73%) and Fanconi anemia (54%) and few alterations in apoptotic machinery. We further identified mutually exclusive and associated mutations/deletions in genes involved in the MAPK and p53 pathways as well as in chromatin regulator/modifier genes. Finally, by combining the gene expression profile, gene mutation, gene deletion, and drug response, we demonstrated that several targeted drugs overcome or bypass some mutations. Conclusions With this work, we retrieved genomic alterations of HMCLs, highlighting that they display numerous and unprecedented abnormalities, especially in DNA regulation and repair pathways. Furthermore, we demonstrate that HMCLs are a reliable model for drug screening for refractory patients at diagnosis or at relapse.