Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma

  1. Jose I. Martin-Subero2,4,5,14,16
  1. 1Centro de Investigación Médica Aplicada (CIMA), IDISNA, 31008 Pamplona, Spain;
  2. 2Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, 28029 Madrid, Spain;
  3. 3Fundació Clínic per a la Recerca Biomèdica, 08036 Barcelona, Spain;
  4. 4Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain;
  5. 5Departamento de Fundamentos Clínicos, Universitat de Barcelona, 08036 Barcelona, Spain;
  6. 6Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA;
  7. 7Clínica Universidad de Navarra, 31008 Pamplona, Spain;
  8. 8Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida 32610, USA;
  9. 9Radboud Institute for Molecular Life Sciences, 6525 GA Nijmegen, Netherlands;
  10. 10Department of Hematology & BMT, Hamad Medical Corporation, NCCCR, Doha, Qatar;
  11. 11European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton CB10 1SD, United Kingdom;
  12. 12CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain;
  13. 13Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA;
  14. 14Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
  • Corresponding authors: xaguirre{at}unav.es, fprosper{at}unav.es, imartins{at}clinic.cat

    • Abstract

    Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.

    Footnotes

    • ↵15 Co-first authors.

    • ↵16 Co-senior authors.

    • [Supplemental material is available for this article.]

    • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.265520.120.

    • Freely available online through the Genome Research Open Access option.

    • Received May 8, 2020.
    • Accepted August 7, 2020.

    This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.

    | Table of Contents
    OPEN ACCESS ARTICLE

    This Article

    1. Published in Advance August 20, 2020, doi: 10.1101/gr.265520.120 Genome Res. 30: 1217-1227 © 2020 Ordoñez et al.; Published by Cold Spring Harbor Laboratory Press

    Article Category

    ORCID

    1. Profile for Gut, I.http://orcid.org/0000-0001-7219-632X

    Share

    Preprint Server



    Current Issue

    1. April 2024, 34 (4)
    1. Current Issue
    1. Alert me to new issues of Genome Research