C to U RNA editing of MFN1 is regulated by ADARB1 and associates with favourable prognosis in chronic lymphocytic leukemia

Cytidine to uridine (C-to-U) as well as adenosine to inosine (A-to-I) RNA editing denotes the posttranscriptional modification of RNA by specialized RNA deaminases. As RNA editing alters the sequence of the RNA, it can affect splicing, stability, miRNA binding and may also lead to recoding of the translated protein. Recently, we analysed recoding A-to-I RNA editing in chronic lymphocytic leukaemia (CLL) and could define prognostically relevant editing patterns. However, disease relevant C-to-U RNA editing in CLL remained unexplored. In this study, we examined C-to-U RNA editing in CLL and discovered a recoding RNA editing site within the MFN1 gene (hg38; chr3:179,375,230), which has recently been described as RNA editing site in brain samples. We found that MFN1 editing was not only present in CLL samples but also in naive B cell subsets, primarily occurred at unspliced RNA and correlated with intron retention. We further identified catalytically active ADARB1 as an essential regulator for MFN1 editing. Finally, MFN1 editing correlated with prolonged time to treatment and overall survival in CLL patients. Summarizing, we identified a novel ADARB1 function as C to U editing regulator, which regulates MFN1 splicing and MFN1 S329L recoding with pathogenic relevance in CLL.