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

Journal article


Alvarez-Benayas, J., Trasanidis, N., Katsarou, A., Ponnusamy, K., Chaidos, A., May, P.C., Xiao, X., Bua, M., Atta, M., Roberts, I., Auner, H.W., Hatjiharissi, E., Papaioannou, M., Caputo Galarce, V., Sudbery, I.M. and Karadimitris, A. (2021). Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma. Nature Communications. 12, p. 5450. https://doi.org/10.1038/s41467-021-25704-2
AuthorsAlvarez-Benayas, J., Trasanidis, N., Katsarou, A., Ponnusamy, K., Chaidos, A., May, P.C., Xiao, X., Bua, M., Atta, M., Roberts, I., Auner, H.W., Hatjiharissi, E., Papaioannou, M., Caputo Galarce, V., Sudbery, I.M. and Karadimitris, A.
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.

KeywordsMultiple Myeloma, epigenetics, gene regulation
Year2021
JournalNature Communications
Journal citation12, p. 5450
PublisherSpringer
ISSN 2041-1723
Digital Object Identifier (DOI)https://doi.org/10.1038/s41467-021-25704-2
Web address (URL)https://pubmed.ncbi.nlm.nih.gov/34521827/
Publication dates
Print14 Sep 2021
Publication process dates
Accepted17 Aug 2021
Deposited14 Apr 2023
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Open
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