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Title: Myeloma-specific superenhancers affect genes of biological and clinical relevance in myeloma
Authors: Jia, Yunlu
Zhou, Jianbiao
Tan, Tze King 
Chung, Tae-Hoon
Wong, Regina Wan Ju 
Chooi, Jing-Yuan 
Lim, Julia Sze Lynn 
Sanda, Takaomi 
Ooi, Melissa
De Mel, Sanjay
Soekojo, Cinnie
Chen, Yongxia
Zhang, Enfan
Cai, Zhen
Shen, Peng
Ruan, Jian
Chng, Wee-Joo 
Keywords: Science & Technology
Life Sciences & Biomedicine
Issue Date: 12-Feb-2021
Citation: Jia, Yunlu, Zhou, Jianbiao, Tan, Tze King, Chung, Tae-Hoon, Wong, Regina Wan Ju, Chooi, Jing-Yuan, Lim, Julia Sze Lynn, Sanda, Takaomi, Ooi, Melissa, De Mel, Sanjay, Soekojo, Cinnie, Chen, Yongxia, Zhang, Enfan, Cai, Zhen, Shen, Peng, Ruan, Jian, Chng, Wee-Joo (2021-02-12). Myeloma-specific superenhancers affect genes of biological and clinical relevance in myeloma. BLOOD CANCER JOURNAL 11 (2). ScholarBank@NUS Repository.
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.
ISSN: 20445385
DOI: 10.1038/s41408-021-00421-7
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