Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma
- Raquel Ordonez1,
- Marta Kulis2,
- Nuria Russinol2,
- Vicente Chapaprieta3,
- Arantxa Carrasco-Leon1,
- Beatriz Garcia-Torre2,
- Stella Charampopoulou2,
- Guillem Clot4,
- Renee Beekman4,
- Cem Meydan5,
- Marti Duran-Ferrer4,
- Nuria Verdaguer-Dot4,
- Roser Vilarrasa-Blasi4,
- Paula Soler-Vila2,
- Leire Garate6,
- Estibaliz Miranda1,
- Edurne San Jose-Eneriz1,
- Juan Roberto Rodriguez-Madoz1,
- Teresa Ezponda1,
- Rebeca Martinez-Turrilas1,
- Amaia Vilas-Zornoza1,
- David Lara-Astiaso1,
- Daphne Dupere-Richer7,
- Joost HA Martens8,
- Halima El-Omri9,
- Ruba Y Taha9,
- Maria Jose Calasanz1,
- Bruno Paiva1,
- Jesus San Miguel6,
- Paul HA Flicek10,
- Ivo Glynne Gut11,
- Ari Melnick5,
- Constantine S. Mitsiades12,
- Jonathan D. Licht7,
- Elias Campo2,
- Hendrik G. Stunnenberg13,
- Xabier Agirre1,
- Felipe Prosper6 and
- Ignacio Martin-Subero4,14
- 1 CIMA;
- 2 Fundacio Clinic per a la Recerca Biomedica;
- 3 Universitat de Barcelona;
- 4 Institut d Investigacions Biomediques August Pi I Sunyer (IDIBAPS);
- 5 Weill Cornell Medical College;
- 6 Clinica Universidad de Navarra;
- 7 University of Florida Health Cancer Center;
- 8 NCMLS;
- 9 Hamad Medical Corporation, NCCCR;
- 10 European Bioinformatics Institute;
- 11 Centro Nacional de Analisis Genomico, Center for Genomic Regulation;
- 12 Dana-Farber Cancer Institute, Harvard Medical School;
- 13 Radboud Institute for Molecular Life Sciences
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 upregulated 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 indicates that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.
- Received May 8, 2020.
- Accepted August 7, 2020.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International license), as described at http://creativecommons.org/licenses/by/4.0/.
