ADAR2-repressed RNA editing: a novel mechanism contributing to t (8:21) AML leukemogenesis

Abstract

In the past decade, adenosine to inosine (A-to-I) RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes ADAR1 and ADAR2, has been shown to contribute to the development and progression of multiple cancers; however, very little is known about its role in acute myeloid leukemia (AML) - the second most common type of leukemia making up 31% of all adult leukemia cases. Here, we found that ADAR2, but not ADAR1 and ADAR3, is specifically downregulated in core binding factor (CBF) AML with t(8;21) or inv(16). In t(8;21) AML, RUNX1-driven transcription of ADAR2 transcripts was found to be repressed by the RUNX1-ETO fusion protein. Forced overexpression of two ADAR2-regulated RNA editing targets COPA and COG3 indeed inhibits clonogenic growth of human t(8;21) AML cells. Further in vivo animal studies confirmed that ADAR2 could suppress leukemogenesis of t(8;21) AML through its RNA binding and editing capabilities. Our results suggest a novel RNA editing-mediated mechanism leading to t(8,12) AML.

The RNA editing landscape in acute myeloid leukemia reveals associations with disease mutations and clinical outcome

“…However, as in the TCGA AML cohort, we could further replicate significant differences in RNA editing levels, across AML genotypes within the BeatAML patient samples (p value = 0.036) ( Figure S1 B). As has been shown in an earlier study across AML cell lines and patient samples, 20 we observed ADAR2 ( Figure S1 C), but not ADAR1 ( Figure 3 E), to be differentially expressed between different AML genotypes.…”

“…Tenen and colleagues have experimentally demonstrated RUNX1-ETO repression of ADAR2 expression and proposed a mechanism whereby hypo-editing of specific transcripts by ADAR2 was implicated in the pathogenesis of t(8; 21) AMLs. 20 We did not observe a general correlation of ADAR2 with the AEI ( Figure S1 A), but did observe a distinct pattern of associations between ADAR1 and ADAR2 with AEI across each AML mutation subtypes ( Figure S1 G) suggesting individual interactions of ADAR enzymes with specific mutations in AML subgroups. Further studies are warranted to identify the potential interactions of ADARs with disease-causing mutations.…”

“…These differential expression patterns of ADAR1 and ADAR2 are further confirmed by a recent study exploring the functional role of RNA editing mediated by ADAR2 in the leukemogenesis in patients carrying t(8; 21) or inv16 mutations. 20 However, unlike for ADAR1, no correlation was noted between ADAR2 levels and the AEI ( Figure S1 A)

Figure 3 Differential editing in AML (A) Boxplots of Alu editing index (AEI) between AML patient samples (red) and healthy controls (blue) from BeatAML cohort. (B) Boxplots of ADAR1 gene expression (CPM) between AML patient samples (red) healthy controls (blue) from BeatAML cohort.

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