Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma
Raquel Ordonez, Marta Kulis, Nuria Russinol, Vicente Chapaprieta, Arantxa Carrasco-Leon, Beatriz Garcia-Torre, Stella Charampopoulou, Guillem Clot, Renee Beekman, Cem Meydan, Marti Duran-Ferrer, Nuria Verdaguer-Dot, Roser Vilarrasa-Blasi, Paula Soler-Vila, Leire Garate, Estibaliz Miranda, Edurne San Jose-Eneriz, Juan Roberto Rodriguez-Madoz, Teresa Ezponda, Rebeca Martinez-Turrilas, Amaia Vilas-Zornoza, David Lara-Astiaso, Daphne Dupere-Richer, Joost Ha Martens, Halima El-Omri, Ruba Y Taha, Maria Jose Calasanz, Bruno Paiva, Jesus San Miguel, Paul Ha Flicek, Ivo Glynne Gut, Ari Melnick, Constantine S Mitsiades, Jonathan D Licht, Elias Campo, Hendrik G Stunnenberg, Xabier Agirre, Felipe Prosper, Ignacio Martin-Subero
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.
CITA DEL ARTÍCULO Genome Res . 2020 Aug 20;gr.265520.120.