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.
© 2021. The Author(s).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / pathology
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Carcinogenesis / genetics*
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Case-Control Studies
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Cell Line, Tumor
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Chromatin / chemistry
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Chromatin / metabolism
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Cyclin D1 / genetics*
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Cyclin D1 / metabolism
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Cyclin D2 / genetics*
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Cyclin D2 / metabolism
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Enhancer Elements, Genetic
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic*
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Gene Regulatory Networks
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / mortality
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Multiple Myeloma / genetics*
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Multiple Myeloma / metabolism
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Multiple Myeloma / mortality
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Multiple Myeloma / pathology
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Plasma Cells / metabolism
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Plasma Cells / pathology
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Proto-Oncogene Proteins c-maf / genetics
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Proto-Oncogene Proteins c-maf / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Survival Analysis
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Transcriptome*
Substances
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CCND1 protein, human
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CCND2 protein, human
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Chromatin
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Cyclin D2
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MAF protein, human
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Proto-Oncogene Proteins c-maf
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Repressor Proteins
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Cyclin D1
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Histone-Lysine N-Methyltransferase
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NSD2 protein, human