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Aberrant hyperediting of myeloma transcriptome by ADAR1 confers oncogenicity and is a marker of poor prognosis

Phaik Ju Teoh, Omer An, Tae-Hoon Chung, Jing Yuan Chooi, Sabrina H.M. Toh, Shuangyi Fan, Wilson Wang, Bryan T.H. Koh, Melissa J. Fullwood, Melissa G. Ooi, Sanjay de Mel, Cinnie Y. Soekojo, Leilei Chen, Siok Bian Ng, Henry Yang and Wee Joo Chng

Key points

  • The integrity of the MM transcriptome is compromised by ADAR1 overexpression, conferring oncogenic events in an editing-dependent manner.

  • NEIL1 is an important ADAR1 editing target and its recoded protein has a defective functional capacity and gain-of-function properties.

Abstract

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 till 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 post-transcriptional mechanism in human physiology and the biological implication of its abnormality, especially at the global level, is underexplored in MM. In this study, we seek to define the biological implications of RNA editing and how it contributes to MM pathogenesis. Herein, we identified that the MM transcriptome is aberrantly hyper-edited, owing to the overexpression of ADAR1. These events were associated with patients’ survival independently 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 gain-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.

  • Submitted February 13, 2018.
  • Accepted July 25, 2018.