Abstract
Multiple myeloma (MM) is an aggressive plasma cell neoplasm characterized by genomic heterogeneity. Superenhancers (SEs) are defined as large clusters of enhancers in close genomic proximity, which regulate genes for maintaining cellular identity and promote oncogenic transcription to which cancer cells highly addicted. Here, we analyzed cis-regulatory elements in MM samples with H3K27ac ChIP-seq, to identify novel SE-associated genes involved in the myeloma pathogenesis. SEs and their associated genes in cancerous tissue were compared with the control samples, and we found SE analysis alone uncovered cell-lineage-specific transcription factors and well-known oncogenes ST3GAL6 and ADM. Using a transcriptional CDK7 inhibitor, THZ1, coupled with H3K27ac ChlP-seq, we identified MAGI2 as a novel SE-associated gene of myeloma cells. Elevated MAGI2 was related to myelomagenesis with gradual increased expression from MGUS, SMM to newly diagnosed and relapsed MM. High prevalence of MAGI2 was also associated with poor survival of MM patients. Importantly, inhibition of the SE activity associated with MAGI2 decreased MAGI2 expression, inhibited cell growth and induced cell apoptosis. Mechanistically, we revealed that the oncogenic transcription factor, MAF, directly bound to the SE region and activated gene transcription. In summary, the discoveries of these acquired SEs-associated genes and the novel mechanism by which they are regulated provide new insights into MM biology and MAGI2-MAF-SE regulatory circuit offer potential novel targets for disease treatment.
Highlights
Multiple myeloma (MM) is characterized by neoplastic proliferation of plasma cells in the bone marrow, which originate from the post-germinal lymphoid B-cell lineage[1]
SE elements are highly occupied by active enhancer marks (H3K27ac, H3K4me1), mediator complex (MED), P300, bromodomain-containing protein 4 (BRD4), cyclindependent kinase 7 (CDK7), and master transcription factors (TFs)
Samples and cell lines To investigate the SE profiles in MM, H3K27ac chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) was performed on selected untreated patient-derived MM samples (MM 1–10) and human myeloma cell lines (HMCLs) (H929, KMS11, KMS28BM, JJN3, RPMI8226, KMS12, and U266) with different known translocations
Summary
Multiple myeloma (MM) is characterized by neoplastic proliferation of plasma cells in the bone marrow, which originate from the post-germinal lymphoid B-cell lineage[1]. The dissection of the molecular landscape of MM would lead to a better understanding of the disease biology and the development of more effective therapeutic options. Enhancers are distal DNA regulatory elements and central regulators of precisely gene expression programs[5]. Accumulating evidence has demonstrated that transcriptions of key oncogenes and maintenance of cancer cell identity are driven by large clusters of enhancers, called superenhancers (SEs)[6,7]. SE elements are highly occupied by active enhancer marks (H3K27ac, H3K4me1), mediator complex (MED), P300, bromodomain-containing protein 4 (BRD4), cyclindependent kinase 7 (CDK7), and master transcription factors (TFs). Previous studies revealed that SEs facilitated high-level transcription of key regulators in MM cell state, such as IGLL5, MYC, IRF4, and PRDM1/BLIMP-18,9. A recent combinatorial analysis of gene expression, open chromatin, and enhancer landscape further revealed the
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