The context-dependent role of the dsRNA response in linking A-to-I editing and ADAR to normal hematopoiesis and leukemia.

Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminase acting on RNA (ADAR), contributes to cellular RNA homeostasis. By recoding protein, inducing alternative splicing and regulating non-coding RNAs, ADAR-mediated editing influences diverse biological processes including development, homeostasis and pathogenesis. In particular, ADAR-mediated A-to-I editing prevents endogenous double-stranded RNAs from improperly activating pattern recognition receptors and downstream innate immune response (dsRNA response), thereby modulating immune homeostasis in a context-dependent manner. Compelling evidence from human studies and animal models implicates ADAR-mediated A-to-I editing in key hematological processes including embryonic and adult hematopoiesis. Notably, dysregulated ADAR functions and aberrant A-to-I editing are increasingly associated with leukemia pathogenesis and progression, thereby exihibiting novel clinical potentials. Given the intimate crosstalk between the hematological and immune systems, it is likely that ADAR's immunosuppressive function mediates these pleiotropic effects of hematological A-to-I editing. In this review, we synthesize current knowledge on A-to-I editing and ADAR in normal hematopoiesis and leukemia. We then reinterpret these findings from an immunological perspective. We highlight the context-dependence of the ADAR1-dsRNA response axis, and characterize it from three perspectives: 1) the shift in axis requirement from normal to malignant states; 2) the involvement of distinct dsRNA sensor(s); 3) the relative hierarchy between editing-dependent mechanism and editing-independent mechanism. Specifically, we propose that the axis is generally indispensable for normal hematopoiesis, whereas its requirement may exhibit intra-leukemia and inter-leukemia heterogeneity. Based on this heterogeneity, we further discuss the diverse translational potentials of this axis, including therapeutic strategies, resistance biomarkers and prognostic predictors. Finally, we identify key theoretical gaps and methodological limitations in exploring this axis, hoping to inspire novel research directions and advance clinical management for leukemia.