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

Author/s: Raquel Ordoñez, Marta Kulis, Nuria Russiñol, Vicente Chapaprieta, Arantxa Carrasco-Leon, Beatriz García-Torre, Stella Charampopoulou, 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-Turrilas, Amaia 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 and Jose I. 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 co-regulated adjacent genes. Among target genes upregulated by this process, we found members of the NOTCH, NFkB, mTOR1 signaling and p53 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.

Additional information

UCSC tracks

Please, use this link to access the MM Referece Epigenome tracks in the UCSC genome browser. The presented tracks are briefly described in this document.


Additional results can be found in the next table.

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MM & B cells

chromatin states

Assignment of 12 different chromatin

states in 200 base pair bins (GRCh38)

using the chromHMM software

50M Link

Normalized signal intensities

of MM reference epigenome &

B cells for RNA-seq, H3K27ac,

H3K4me1, H3K4me3,

H3K9me3, H3K27me3, 

H3K36me3 & ATAC-seq

Variance stabilizing transformed data

signals as determined using DEseq2

in consensus peaks (GRCh38) for the

different histone marks and ATAC-seq.


FPKM gene expression values for

RNA-seq (gencode22).

73M Link

MM reference epigenome &

B cells methylation

DNA methylation estimates (GRCh38)

determined by whole genome bisulfite

sequencing. The data is divided into

hypo and hypermethylated CpGs in

multiple myeloma.

56M Link