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Multiple myeloma gammopathies

MYC dysregulation in the progression of multiple myeloma

Leukemia volume 34, pages 322–326 (2020)Cite this article

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Multiple myeloma (MM) is a plasma cell malignancy preceded by a premalignant stage, named monoclonal gammopathy of undetermined significance (MGUS), and often a smoldering phase (SMM) [1, 2]. Primary events, which include recurrent translocations of the IgH locus and hyperdiploidy, occur early in pathogenesis, and are followed by the acquisition of secondary genetic events such as MYC structural variants (SVs), mutations that activate the RAS or NFkB pathways, mutations of DIS3 or FAM46C that drive precursor stages of disease toward MM [3,4,5,6]. Whole-exome sequencing (WES) studies comparing serial MGUS/SMM and MM samples indicate clonal stability, and no significant increase in mutational load in patients that progress rapidly to MM [7]. In contrast, in 33 unselected MGUS patients single-nucleotide variants (SNVs) were less frequent, and no MYC translocations identified [8].

To study the role of MYC in myeloma, we performed an integrated genomic analysis of 612 newly diagnosed multiple myeloma (NDMM) patients enrolled in the CoMMpass study, as well as targeted sequencing of 23 patients with MGUS and 90 patients with SMM. We identified MYC SV in 42% of NDMM, including the majority of Hyperdiploid (HRD) (57%), and a quarter of MM with primary IgH translocations. The majority of these rearrangements resulted in juxtaposition of a super-enhancer (SE) and/or stretch enhancer adjacent to MYC, with one-third involving an Ig super-enhancer, one-third involving another recurrent super/stretch enhancer, and the remaining third split between non-recurrent super/stretch enhancers, no identified super/stretch enhancer, or rearrangements wholly confined to the region telomeric to MYC, frequently duplications with no exogenous sequences present (Tables S1a, b and  S2–4). The IgH MYC rearrangements often were complex—sometimes involving duplications and three or more chromosomes—and the IgH breakpoints were often within or near the 3ʹ SE regions, suggesting a different timing or mechanism than the primary IgH translocations.

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Acknowledgements

This work was supported by the National Cancer Institute under award numbers R01CA195688 (PLB), P50CA186781 (PLB), U54CA224018 (AKS), and the Intramural Research Program, Center for Cancer Research (WMK). Additional support for researchers from Health Research Board Ireland HPF-2015-1007 (NK) and Norwegian Cancer Society (5788886) (KM).

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  1. These authors contributed equally: Kristine Misund, Niamh Keane

Authors and Affiliations

  1. Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA

    Kristine Misund, Niamh Keane, Caleb K. Stein, Grady Day, Seth Welsh, Scott A. Van Wier, Daniel L. Riggs, Greg Ahmann, Marta Chesi, Veronica Gonzalez-Calle, Rafael Fonseca, A. Keith Stewart, Esteban Braggio & P. Leif Bergsagel

  2. Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    Kristine Misund

  3. National University of Ireland, Galway, Ireland

    Niamh Keane & Michael O’Dwyer

  4. Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA

    Yan W. Asmann

  5. Department of Medicine, Mayo Clinic, Rochester, MN, USA

    David S. Viswanatha, Shaji K. Kumar, Angela Dispenzieri, Robert A. Kyle & S. Vincent Rajkumar

  6. Department of Hematology and Oncology, University Hospital Würzburg, Würzburg, Germany

    K. Martin Kortüm

  7. Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA

    J. Jonathan Keats

  8. Center for Cancer Research, National Institute of Health, Bethesda, MD, USA

    W. Michael Kuehl

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  1. Kristine Misund
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Consortia

MMRF CoMMpass Network

Contributions

PLB, WMK, and KM originated concept and design of investigation, KMK, EB developed custom capture panel, SVW FISH analysis, GA primary samples, YWA, GD, WMK, PLB developed additional bioinformatics methods, NK, KM, CKS, PLB, WMK performed analyses, and NK, KM, CKS, WMK, PLB composed manuscript. We thank JK and MMRF research network for their work on CoMMpass. All authors read and approved of final manuscript.

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Correspondence to P. Leif Bergsagel.

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Misund, K., Keane, N., Stein, C.K. et al. MYC dysregulation in the progression of multiple myeloma. Leukemia 34, 322–326 (2020). https://doi.org/10.1038/s41375-019-0543-4

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