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Myeloma-specific superenhancers affect genes of biological and clinical relevance in myeloma.
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.
Afiliação
  • Jia Y; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Republic of Singapore.
  • Zhou J; Department of Medical oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Tan TK; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Republic of Singapore.
  • Chung TH; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Republic of Singapore.
  • Wong RWJ; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Republic of Singapore.
  • Chooi JY; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Republic of Singapore.
  • Lim JSL; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Republic of Singapore.
  • Sanda T; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Republic of Singapore.
  • Ooi M; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Republic of Singapore.
  • De Mel S; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Republic of Singapore.
  • Soekojo C; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Republic of Singapore.
  • Chen Y; Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), 1E, Kent Ridge Road, Singapore, 119228, Republic of Singapore.
  • Zhang E; Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), 1E, Kent Ridge Road, Singapore, 119228, Republic of Singapore.
  • Cai Z; Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), 1E, Kent Ridge Road, Singapore, 119228, Republic of Singapore.
  • Shen P; Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
  • Ruan J; Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • Chng WJ; Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
Blood Cancer J ; 11(2): 32, 2021 02 12.
Article em En | MEDLINE | ID: mdl-33579893
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Regulação Neoplásica da Expressão Gênica / Mieloma Múltiplo Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Regulação Neoplásica da Expressão Gênica / Mieloma Múltiplo Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article