PF567 CHROMATIN ACTIVATION AS A UNIFYING PRINCIPLE UNDERLYING PATHOGENIC MECHANISMS IN MULTIPLE MYELOMA
Authors: Ordoñez R. , Kulis M. , Russiñol N. , Chapaprieta V. , Beekman R. , Meydan C. , Duran‐Ferrer M. , Verdaguer‐Dot N. , Clot G. , Vilarrasa‐Blasi R. , Garate L. , Miranda E. , Carrasco A. , Ezponda T. , Martens J.H.A. , El‐Omri H. , Taha R.Y. , Calasanz M.J. , Paiva B. , Miguel J. San , Flicek P. , Gut I. , Melnick A. , Mitsiades C.S. , Licht J.D. , Campo E. , Stunnenberg H.G. , Agirre X. , Martin‐Subero J.I. , Prósper F. 
Published: June 2019

Background:

How a quiescent, terminally differentiated plasma cell transforms into an aggressive and lethal disease such as multiple myeloma (MM) remains a scientific puzzle. The abnormal genomic landscape of MM patients has been previously characterized but has not been fully capable of explaining the pathogenesis of the disease. Furthermore, MM is a remarkably heterogeneous disease with no unifying transforming mechanism. Recently, breakthrough discoveries in the epigenetics field have transformed our understanding of neoplastic transformation. However, the chromatin regulatory network underlying MM onset and progression has just started to be characterized.

Aims:

To identify the core epigenetic mechanisms underlying myelomagenesis by integrating a multi‐omics characterization of MM patients in the context of normal B cell differentiation.

Methods:

We have generated and integrated genome‐wide maps of multiple epigenetic layers in human primary plasma cells from MM patients and, as healthy controls, different stages of B cell differentiation, including naïve B cells, germinal center B cells, memory B cells and plasma cells. These have included six histone modifications with non‐overlapping functions (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H2K27me3 and H3K9me3), chromatin accessibility (ATAC‐Seq), DNA methylation (WGBS) and gene expression (RNA‐Seq).

Results:

Through a multi‐omics view of the MM epigenome in the context of normal B cell differentiation, we have identified that MM, although genetically heterogeneous, shares a core epigenomic MM‐specific signature characterized by an extensive de novo chromatin activation of regulatory elements. When further characterized, we found that chromatin activation and abnormal accessibility landscape lead to an extensive perturbation of the MM transcriptome, associated with different key mechanisms for myelomagenesis. On one hand, the target genes of the activated regulatory regions were remarkably enriched in multiple pathways previously associated with MM, such as NOTCH, NFkB, mTOR1 signaling and p53 signaling pathways. Other activated genes included sets involved in biological processes associated with osteoblast differentiation and response to oxidative stress, suggesting a chromatin‐basis underlying the pathogenesis of MM. We functionally validated the pathogenic impact of such chromatin activation by defining MM specific distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status, key for MM cell survival and proliferation. On the other hand, we have studied blocks of closely linked genes that become denovoactive in MM. We functionally analyzed the impact of two of these co‐expressed genes, PRDM5 and NDNF, and validated that only the former has an impact on cell growth. Furthermore, we could demonstrate PRDM5 is involved in cellular responses to DNA damage and protein synthesis stresses. Our results support the concept that protection against different types of cellular stress is a key element for MM cell survival, and that the neoplastic plasma cells may in part achieve this stress‐resistant phenotype through aberrant de novoc hromatin activation.

Summary/Conclusion:

Together, this study proposes a new model to understand the pathogenesis of MM, indicating that extensive chromatin activation seems to be a unifying principle underlying multiple pathogenic mechanisms in MM, which suggests that epigenetic drugs such as BET inhibitors may be appropriate as a backbone treatment for patients affected with this aggressive disease.