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Title: Aberrant hyperediting of the myeloma transcriptome by ADAR1 confers oncogenicity and is a marker of poor prognosis
Authors: Teoh, Phaik Ju 
An, Omer 
Chung, Tae-Hoon 
Chooi, Jing Yuan 
Toh, Sabrina HM 
Fan, Shuangyi 
Wang, Wilson 
Koh, Bryan TH
Fullwood, Melissa J 
Ooi, Melissa G 
de Mel, Sanjay
Soekojo, Cinnie Y
Chen, Leilei 
Ng, Siok Bian 
Yang, Henry 
Chng, Wee Joo 
Keywords: Science & Technology
Life Sciences & Biomedicine
Issue Date: 20-Sep-2018
Citation: Teoh, Phaik Ju, An, Omer, Chung, Tae-Hoon, Chooi, Jing Yuan, Toh, Sabrina HM, Fan, Shuangyi, Wang, Wilson, Koh, Bryan TH, Fullwood, Melissa J, Ooi, Melissa G, de Mel, Sanjay, Soekojo, Cinnie Y, Chen, Leilei, Ng, Siok Bian, Yang, Henry, Chng, Wee Joo (2018-09-20). Aberrant hyperediting of the myeloma transcriptome by ADAR1 confers oncogenicity and is a marker of poor prognosis. BLOOD 132 (12) : 1304-1317. ScholarBank@NUS Repository.
Abstract: © 2018 by The American Society of Hematology. DNA alterations have been extensively reported in multiple myeloma (MM); however, they cannot yet fully explain all the biological and molecular abnormalities in MM, which remains to this day an incurable disease with eventual emergence of refractory disease. Recent years have seen abnormalities at the RNA levels being reported to possess potential biological relevance in cancers. ADAR1-mediated A-to-I editing is an important posttranscriptional mechanism in human physiology, and the biological implication of its abnormality, especially at the global level, is underexplored in MM. In this study, we define the biological implications of A-to-I editing and how it contributes to MM pathogenesis. Here, we identified that the MM transcriptome is aberrantly hyperedited because of the overexpression of ADAR1. These events were associated with patients’ survival independent of 1q21 amplifications and could affect patients’ responsiveness to different treatment regimes. Our functional assays established ADAR1 to be oncogenic, driving cellular growth and proliferation in an editing-dependent manner. In addition, we identified NEIL1 (base-excision repair gene) as an essential and a ubiquitously edited ADAR1 target in MM. The recoded NEIL1 protein showed defective oxidative damage repair capacity and loss-of-function properties. Collectively, our data demonstrated that ADAR1-mediated A-to-I editing is both clinically and biologically relevant in MM. These data unraveled novel insights into MM molecular pathogenesis at the global RNA level.
Source Title: BLOOD
ISSN: 0006-4971
DOI: 10.1182/blood-2018-02-832576
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