RNA editing as diversifier of genetic information in Leukemia

Implications of RNA editing on chronic lymphocytic leukemia

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Genetic lesions are a major driver of cancer initiation, development and progression, as they affect gene expression and alter protein function. While aberrations of the DNA are considered as main cause for protein recoding, genetic information is also altered by RNA editing, a posttranscriptional mechanism comprising adenosine to inosine (a guanosine analogue) deamination by ADAR enzymes (adenosine deaminase acting on RNA) as the prevailing type of editing[1].

ADAR dependent RNA editing occurs in all metazoan and every cell type has its own specific RNA editing pattern, affecting a distinct set of genes and editing sites. While many editing events are synonymous, some of them are protein-recoding or impact RNA stability. Apart from gene-recoding, RNA editing affects repetitive, non-coding transcribed regions (mostly Alu-repeats), which is important to avoid uncontrolled inflammation, as non-edited transcribed Alu repeats would be recognized by intracellular RNA sensors such as MDA5[1, 2].

In our recent study, we investigated RNA editing in chronic lymphocytic leukemia (CLL) and normal B cell subsets. The first intriguing results of our study was that in contrast to most other cancer types, CLL cells had decreased editing activity compared to their normal counterpart cell types. Furthermore, we found that normal B cell subsets (naïve B cells, IgM positive memory B cells and class switched memory B cells) had their inherent, highly specific pattern of non-synonymous editing events. In contrast, CLL cells had a high variability in RNA editing and while the similar set of genes as in normal B cell subsets was also edited in CLL cells, the editing frequency was totally different and revealed a high interpatient variability, which allowed clustering of CLL patients into defined editing-groups. These editing groups revealed also distinct clinical parameters and prognosis. When we impeded RNA editing in a CLL cell line by knocking out ADAR, we found increased sensitivity towards fludarabine and ibrutinib treatment in vitro, aside of decreased steady-state viability and cell cycling. In addition, ADAR loss resulted in perturbed gene expression profiles.

Our results have several important implications: first, RNA editing is an important diversifier of genetic information also in CLL, contributing to a specific gene(variant) expression profile. Second, the results show that interference with RNA editing in patients could likely synergize with current CLL drugs such as ibrutinib and could thus potentially maximize complete response rates while minimizing treatment resistance. Finally, inflammation is a major driver of RNA editing[1] and the fact that overall RNA editing activity is lower in CLL cells compared to normal B cell subsets may point to a generally low immune pressure put on CLL cells, corroborating the reported low efficacy of immune checkpoint inhibitors in CLL. Hence, we hypothesize that interference with RNA editing could not only increase sensitivity towards CLL drugs, but also the sensitivity towards immune checkpoint therapy approaches in CLL.

 

References

  1. Eisenberg, E. and E.Y. Levanon, A-to-I RNA editing - immune protector and transcriptome diversifier. Nat Rev Genet, 2018. 19(8): p. 473-490.
  2. Liddicoat, B.J., R. Piskol, A.M. Chalk, G. Ramaswami, M. Higuchi, J.C. Hartner, et al., RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science, 2015. 349(6252): p. 1115-20.

Roland Geisberger

PI, SCRI-LIMCR

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