Unveil mysterious “super-enhancers” in multiple myeloma

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Multiple myeloma (MM) is an aggressive plasma cell neoplasm characterized by genomic heterogeneity. Super-enhancers (SEs) are regarded as a large trunk of DNA fragments that activate transcription in a “super” strong fashion. Our lab has a long lasting interest in finding a better therapy for MM through characterization of the genomic and epigenomic changes of MM malignant cells (1).

The co-first author of this paper (2), Yunlu Jia, who was a Ph.D student from the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, arrived in our lab for a joint Ph.D program in December 2018. Yunlu was given a task to characterize the mysterious “super-enhancers” in MM and search for new therapeutic targets under the supervision of Dr Jianbiao Zhou, MD, Ph.D. The project was in collaboration with A/Prof Takaomi Sanda in our institute and the bioinformatic analysis was mainly performed by Dr Tze-King Tan, Ph.D.

As the first step, we systematically profiled SEs and their associated genes in MM samples vs normal controls by using H3K27ac ChIP-seq. This SE analysis alone produced a long list of SE associated genes. Among them, we uncovered cell lineage-specific transcription factors (TFs) and well-known oncogenes ST3GAL6 and ADM. This list gave us the confidence to further hunt for high value candidates. Because SE-associated genes are highly sensitive to disruption of transcriptional program, we then generated RNA-seq data from MM cells treated with a transcriptional CDK7 inhibitor, THZ1. When overlapping the RNA-seq and H3K27ac ChlP-seq, we identified MAGI2 as a novel MM specific SE-associated gene. After validating the roles of MAGI2 in MM pathogenesis and its clinical significance, we further performed mechanistic studies and identified the oncogenic TF, MAF, directly bound to the SE associated with MAGI2, and activated its expression (Figure 1).

Figure1. Schematic diagram showing SE-driven MAGI2 activation is dependent, at least partially, on oncogenic transcription factor MAF in MM.

Our results support the strategy that the discoveries of these acquired SEs-associated genes and the novel mechanism by which they are regulated provide new insights into MM biology and offer potential novel targets for disease treatment.

References

  1. Jia Y, Chng WJ, Zhou J. Super-enhancers: critical roles and therapeutic targets in hematologic malignancies. J Hematol Oncol. 2019;12(1):77.
  2. Jia Y, Zhou J, Tan TK, Chung TH, Wong RWJ, Chooi JY, et al. Myeloma specific superenhancers affect genes of biological and clinical relevance in myeloma. Blood Cancer Journal 11, Article number: 32 (2021).

 

Wee Joo Chng

Professor, National University of Singapore