CHROMATIN ACTIVATION AS A UNIFYING PRINCIPLE UNDERLYING PATHOGENIC MECHANISMS IN MULTIPLE MYELOMA
Author(s): ,
Raquel Ordoñez
Affiliations:
Oncohematology,Center for Applied Medical Research (CIMA),Pamplona,Spain
,
Marta Kulis
Affiliations:
Departamento de Fundamentos Clínicos,Universitat de Barcelona,Barcelona,Spain
,
Nuria Russiñol
Affiliations:
Departamento de Fundamentos Clínicos,Universitat de Barcelona,Barcelona,Spain
,
Vicente Chapaprieta
Affiliations:
Departamento de Fundamentos Clínicos,Universitat de Barcelona,Barcelona,Spain
,
Renée Beekman
Affiliations:
Institutd’InvestigacionsBiomèdiques August Pi i Sunyer (IDIBAPS),Barcelona,Spain
,
Cem Meydan
Affiliations:
Dept. of Medicine,Weill Cornell Medical College,New York,United States
,
Martí Duran-Ferrer
Affiliations:
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona,Spain
,
Núria Verdaguer-Dot
Affiliations:
Departamento de Fundamentos Clínicos,Universitat de Barcelona,Barcelona,Spain
,
Guillem Clot
Affiliations:
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona,Spain
,
Roser Vilarrasa-Blasi
Affiliations:
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona,Spain
,
Leire Garate
Affiliations:
Oncohematology,Center for Applied Medical Research (CIMA),Pamplona,Spain
,
Estíbaliz Miranda
Affiliations:
Oncohematology,Center for Applied Medical Research (CIMA),Pamplona,Spain
,
Arantxa Carrasco
Affiliations:
Oncohematology,Center for Applied Medical Research (CIMA),Pamplona,Spain
,
Teresa Ezponda
Affiliations:
Oncohematology,Center for Applied Medical Research (CIMA),Pamplona,Spain
,
Joost H.A. Martens
Affiliations:
Radboud Institute for Molecular Life Sciences,Nijmegen,Netherlands
,
Halima El-Omri
Affiliations:
Department of Hematology & BMT,Hamad Medical Corporation,Doha,Qatar
,
Ruba Y. Taha
Affiliations:
Department of Hematology & BMT,Hamad Medical Corporation,Doha,Qatar
,
María J. Calasanz
Affiliations:
Center for Applied Medical Research (CIMA),Pamplona,Spain
,
Bruno Paiva
Affiliations:
Center for Applied Medical Research (CIMA),Pamplona,Spain
,
Jesús San Miguel
Affiliations:
Clínica Universidad de Navarra,Pamplona,Spain
,
Paul Flicek
Affiliations:
European Molecular Biology Laboratory,European Bioinformatics Institute (EMBL-EBI),Hinxton,United Kingdom
,
Ivo Gut
Affiliations:
Centre for Genomic Regulation (CRG),Barcelona,Spain
,
Ari Melnick
Affiliations:
Dept. of Medicine,Weill Cornell Medical College,New York,United States
,
Constantine S. Mitsiades
Affiliations:
Department of Medical Oncology,Dana-Farber Cancer Institute,Boston,United States
,
Jonathan D. Licht
Affiliations:
University of Florida Health Cancer Center,Gainesville,United States
,
Elias Campo
Affiliations:
Fundació Clínic per a la Recerca Biomèdica,Barcelona,Spain
,
Hendrik G. Stunnenberg
Affiliations:
Radboud Institute for Molecular Life Sciences,Nijmegen,Netherlands
,
Xabier Agirre
Affiliations:
Oncohematology,Center for Applied Medical Research (CIMA),Pamplona,Spain
,
Jose I. Martin-Subero
Affiliations:
Departamento de Fundamentos Clínicos,Universitat de Barcelona,Barcelona,Spain
Felipe Prósper
Affiliations:
Clínica Universidad de Navarra,Pamplona,Spain
EHA Library. Ordoñez R. Jun 14, 2019; 266366; PF567
Raquel Ordoñez
Raquel Ordoñez
Contributions
Abstract

Abstract: PF567

Type: Poster Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 17:30 - 19:00

Location: Poster area

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.

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.

Session topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research

Keyword(s): Epigenetic, Myeloma

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