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Myeloma

Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma

Leukemia volume 28, pages 1725–1735 (2014)Cite this article

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Abstract

MYC locus rearrangements—often complex combinations of translocations, insertions, deletions and inversions—in multiple myeloma (MM) were thought to be a late progression event, which often did not involve immunoglobulin genes. Yet, germinal center activation of MYC expression has been reported to cause progression to MM in an MGUS (monoclonal gammopathy of undetermined significance)-prone mouse strain. Although previously detected in 16% of MM, we find MYC rearrangements in nearly 50% of MM, including smoldering MM, and they are heterogeneous in some cases. Rearrangements reposition MYC near a limited number of genes associated with conventional enhancers, but mostly with super-enhancers (e.g., IGH, IGL, IGK, NSMCE2, TXNDC5, FAM46C, FOXO3, IGJ, PRDM1). MYC rearrangements are associated with a significant increase of MYC expression that is monoallelic, but MM tumors lacking a rearrangement have biallelic MYC expression at significantly higher levels than in MGUS. We also have shown that germinal center activation of MYC does not cause MM in a mouse strain that rarely develops spontaneous MGUS. It appears that increased MYC expression at the MGUS/MM transition usually is biallelic, but sometimes can be monoallelic if there is an MYC rearrangement. Our data suggest that MYC rearrangements, regardless of when they occur during MM pathogenesis, provide one event that contributes to tumor autonomy.

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Acknowledgements

We thank the MMRC for their help in processing samples for this project and making available cytospin slides for FISH, the RNA for selective expression and with the help of Mike Chapman, the list of structural variations in the MYC locus from the MM Genomics Initiative.38 This work is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (WMK); Grants CA83724 (RF), ECOG CA21115T(RF), CA136671 (PLB), CA133966 (PLB), Predolin Foundation, Mayo Clinic Cancer Center and the Mayo Foundation. Rafael Fonseca is a Clinical Investigator of the Damon Runyon Cancer Research Fund.

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Author notes

  1. P L Bergsagel and W M Kuehl: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology Oncology, Mayo Clinic Arizona, Comprehensive Cancer Center, Scottsdale, AZ, USA

    M Affer, M Chesi, K Tamizhmani, V M Garbitt, D L Riggs, S Van Wier, R Fonseca & P L Bergsagel

  2. Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    W D Chen, Y N Demchenko, K Tamizhmani, L A Brents, A V Roschke & W M Kuehl

  3. Translational Genomics Research Institute, Phoenix, AZ, USA

    J J Keats

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Affer, M., Chesi, M., Chen, W. et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia 28, 1725–1735 (2014). https://doi.org/10.1038/leu.2014.70

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