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

Raquel Ordoñez, Marta Kulis, Nuria Russiñol, Vicente Chapaprieta, Arantxa Carrasco-Leon, Beatriz García-Torre, Stella Charalampopoulou, Guillem Clot, Renée Beekman, Cem Meydan, Martí Duran-Ferrer, Núria Verdaguer-Dot, Roser Vilarrasa-Blasi, Paula Soler-Vila, Leire Garate, Estíbaliz Miranda, Edurne San José-Enériz, Juan R. Rodriguez-Madoz, Teresa Ezponda, Rebeca Martínez-TurrilasAmaia Vilas-Zornoza, David Lara-Astiaso, Daphné Dupéré-Richer, Joost H.A. Martens, Halima El-Omri, Ruba Y. Taha, Maria J. Calasanz, Bruno Paiva, Jesus San Miguel, Paul Flicek, Ivo Gut, Ari Melnick, Constantine S. Mitsiades, Jonathan D. Licht, Elias Campo, Hendrik G. Stunnenberg, Xabier Agirre, Felipe Prosper, Jose I. Martin-Subero

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1217-1227
Number of pages11
JournalGenome Research
Volume30
Issue number9
DOIs
Publication statusPublished - Oct 2020
Externally publishedYes

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