MM transcriptome is hyperedited and directly regulated by ADAR1. (A) Total number of editing sites detected across the whole transcriptome (also referred to as global events) in patients from different disease stages. The sequencing platform used was Illumina Hi-Seq 4000. (B) Correlation of global A-to-G editing events with ADAR1 expression in in-house samples (top) and in CoMMpass patients (bottom). (Ci-ii) Overall survival of CoMMpass patients based on differential editing levels (Cii). Multivariate analysis of overall survival in patients according to different prognostic factors. P value in red indicates statistical significance. Amp, amplification; ISS, International Staging System; PI, proliferation index; wt, wild type. (D, top) Validation of ADAR1 knockdown and overexpression in U266 and MM1s, respectively. (Bottom) Fold change in the global A-to-G editing frequency in OCIMY5-ADAR1-WT and OCIMY5-ADAR1-Mut (deaminase mutant) and U266-shADAR1 #1 and #3 relative to EV and shCtrl, respectively. Percentage fold change of A>G events in U266 was calculated with the formula of [(% of events in shADAR #1 or #3−% of events in shCtr)/% of events in shCtr]×100. Percentage-fold change of A>G events in MM1s was calculated with the formula of [(% of events in ADAR1-WT or ADAR1-Mut−% of events in EV)/% of events in EV]×100. (E) A-to-G editing frequency of known ADAR1 targets (MAGT1, SRP9, and PODXL) on ADAR1 knockdown (U266) and overexpression (MM1s), detected by Sanger sequencing. Arrow indicates the site of editing. Green peak represents A nucleotide, and black peak represents G nucleotide.