Myeloma-specific superenhancers affect genes of biological and clinical relevance in myeloma

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.

Super Enhancer-Mediated Upregulation ofHJURPPromotes Growth and Survival of t(4;14)-Positive Multiple Myeloma

“…The vulnerability of these malignancies to CDK7 inhibition was reported to be mediated by SEs-driven oncogenic transcriptional dependencies. Previously, using an integrative analysis of identifying SE landscape by high-throughput H3K27ac chromatin immunoprecipitation platform followed by further filtering those SE-associated genes whose expression are significantly downregulated following THZ1 treatment, we have identified several functionally relevant SE-associated genes in T-cell acute lymphoblastic leukemia and myeloma cells 23,24 . Using a similar strategy, we seek to identify SE-associated genes of functional relevance in t (4;14) myeloma and understand how they are regulated.…”

The novel role of circular RNA ST3GAL6 on blocking gastric cancer malignant behaviors through autophagy regulated by the FOXP2/MET/mTOR axis

“…This is the rst report showing the circular RNA ST3GAL6 can inhibit the malignant progression of gastric cancer. According to previous studies, linear ST3GAL6 is involved in the progression of multiple tumours, including urinary bladder cancer, colorectal cancer and multiple myeloma [35][36][37] , suggesting a potential connection between the two forms. Furthermore, we con rmed the lower expression of circST3GAL6 in GC tissues and its correlation with tumour size and stage, which was expected to be one of the biomarkers for detecting gastric cancer.…”

The Therapeutic Effect of Circular RNA ST3GAL6 on Blocking GC Malignant Behaviors Through Autophagy Regulated by the FOXP2/MET/Mtor Axis

“…According to previous studies, linear ST3GAL6 is involved in the progression of multiple tumours, including urinary bladder cancer, colorectal cancer and multiple myeloma [35][36][37], suggesting a potential connection between the two forms. Furthermore, we con rmed the lower expression of circST3GAL6 in GC tissues and its correlation with tumour size and stage, which was expected to be one of the biomarkers for detecting gastric cancer.…”