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

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.

Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

“…During the development of MM disease, an increased accessibility of chromatin is observed favoring global histone acetylation and chromatin activation [103]. Recent data obtained using a multi-epigenomic approach showed that MM cells are characterized by an aberrant chromatin activation [104]. Among the target genes upregulated by this process, are members of the NFκB and p53 signaling pathways, and response to oxidative stress.…”

“…Moreover, a multi-epigenomics approach demonstrated that an aberrant chromatin activation is a common feature of MM cells. Among the targeted genes activated by this process are genes involved in the response to oxidative stress including TXN [104].…”

The multifunctional role of Notch signaling in multiple myeloma

“…One possibility is that the increase in Notch members is due to genetic mutations. For instance, Notch receptor 2 increases have been associated with translocations t(14;16)(q32;q23) and t(14;20)(q32;q11) [45] . The increased copy number of Notch ligands and receptors has also been linked to trisomies of various chromosomes at which genes of the Notch pathway are located.…”

Role of Polycomb Complexes in Normal and Malignant Plasma Cells

“…MM is a highly heterogeneous disease at the molecular and clinical levels [71][72][73][74]. Epigenetic modifications including DNA methylation, chromatin accessibility, and histone modifications have been reported in MM in association with pathogenic impact [75][76][77][78][79]. Moreover, the many epigenetic alterations observed in MM contribute to this biological heterogeneity and also to treatment resistance [80].…”