Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

• Published in: Nature communications 2019-04, Vol.10 (1), p.1911-13, Article 1911
• Main Authors: Barwick, Benjamin G., Neri, Paola, Bahlis, Nizar J., Nooka, Ajay K., Dhodapkar, Madhav V., Jaye, David L., Hofmeister, Craig C., Kaufman, Jonathan L., Gupta, Vikas A., Auclair, Daniel, Keats, Jonathan J., Lonial, Sagar, Vertino, Paula M., Boise, Lawrence H.
• Format: Article
• Language: English
• Subjects: 45; 45/15; 45/23; 45/91; 631/67/1857; 631/67/1990/804; 631/67/69; Antibodies; Antineoplastic Agents - therapeutic use; Chains; Chromosome translocations; DNA Copy Number Variations; Drug Resistance, Neoplasm - genetics; Drug Resistance, Neoplasm - immunology; Enhancer Elements, Genetic; Enhancers; Gene Expression Regulation, Neoplastic; Genetic Loci; Genome, Human; Health risk assessment; Humanities and Social Sciences; Humans; Ikaros Transcription Factor - genetics; Ikaros Transcription Factor - immunology; Immunoglobulin lambda-Chains - genetics; Immunoglobulins; Immunologic Factors - therapeutic use; Lenalidomide - therapeutic use; Loci; Malignancy; multidisciplinary; Multiple myeloma; Multiple Myeloma - diagnosis; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - mortality; Myc protein; Myeloma Proteins - genetics; Plasma cells; Plasma Cells - immunology; Plasma Cells - pathology; Prognosis; Protein Binding; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - immunology; Recurrence; Risk analysis; Science; Science (multidisciplinary); Survival Analysis; Thalidomide - analogs & derivatives; Thalidomide - therapeutic use; Translocation; Translocation, Genetic; Whole Genome Sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09555-6

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance. Multiple myeloma is frequently characterised by translocation of genes next to the immunoglobulin heavy chain locus. In this study, the authors sequence a large cohort of high risk myeloma samples and find translocations of cMyc to the immunoglobulin heavy chain locus and this is associated with poor prognosis.