Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma

Jaime Alvarez-Benayas, Nikolaos Trasanidis, Alexia Katsarou, Kanagaraju Ponnusamy, Aristeidis Chaidos, Philippa C. May, Xiaolin Xiao, Marco Bua, Maria Atta, Irene A. G. Roberts, Holger W. Auner, Evdoxia Hatjiharissi, Maria Papaioannou, Valentina S. Caputo (), Ian M. Sudbery () and Anastasios Karadimitris ()
Additional contact information
Jaime Alvarez-Benayas: University of Sheffield
Nikolaos Trasanidis: Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London
Alexia Katsarou: Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London
Kanagaraju Ponnusamy: Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London
Aristeidis Chaidos: Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London
Philippa C. May: Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London
Xiaolin Xiao: Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London
Marco Bua: Hammersmith Hospital, Imperial College Healthcare NHS Foundation Trust
Maria Atta: Hammersmith Hospital, Imperial College Healthcare NHS Foundation Trust
Irene A. G. Roberts: MRC Molecular Haematology Unit and Paediatrics, MRC Weatherall Institute of Molecular Medicine
Holger W. Auner: Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London
Evdoxia Hatjiharissi: First Department of Internal Medicine, Division of Haematology, AHEPA University Hospital, Aristotle University of Thessaloniki
Maria Papaioannou: First Department of Internal Medicine, Division of Haematology, AHEPA University Hospital, Aristotle University of Thessaloniki
Valentina S. Caputo: Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London
Ian M. Sudbery: University of Sheffield
Anastasios Karadimitris: Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct myeloma transcriptome profiles are primarily driven by myeloma initiating events (MIE) and converge into a mutually exclusive overexpression of the CCND1 and CCND2 oncogenes. Here, with reference to their normal counterparts, we find that myeloma PC enhanced chromatin accessibility combined with paired transcriptome profiling can classify MIE-defined genetic subgroups. Across and within different MM genetic subgroups, we ascribe regulation of genes and pathways critical for myeloma biology to unique or shared, developmentally activated or de novo formed candidate enhancers. Such enhancers co-opt recruitment of existing transcription factors, which although not transcriptionally deregulated per se, organise aberrant gene regulatory networks that help identify myeloma cell dependencies with prognostic impact. Finally, we identify and validate the critical super-enhancer that regulates ectopic expression of CCND2 in a subset of patients with MM and in chronic lymphocytic leukemia.

Date: 2021
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DOI: 10.1038/s41467-021-25704-2

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