Advances in RNA editing in hematopoiesis and associated malignancies

Abstract Adenosine-to-inosine (A-to-I) RNA editing is a prevalent RNA modification essential for cell survival. The process is catalyzed by the adenosine deaminase acting on RNA (ADAR) enzyme family that converts adenosines in double-stranded RNAs (dsRNAs) into inosines, which are read as guanosines during translation. Deep sequencing has helped to reveal that A-to-I editing occurs across various types of RNAs, affecting their functions. RNA editing detection is now so sophisticated that we can achieve a high level of accuracy and sensitivity to identify low-abundance edited events. Consequently, A-to-I editing has been implicated in various biological processes, including immune and stress responses, cancer progression, and stem cell fate determination. In particular, a crucial role for this process has been recently reported in hematopoietic cell development and hematologic malignancy progression. Results from genetic mouse models have demonstrated the impact of ADARs' catalytic activity on hematopoietic cells, complemented by insights from human cell studies. Meanwhile, clinical studies have implicated ADAR enzymes and RNA editing events in hematologic malignancies and highlighted their potential as prognostic indicators. In this review, we outline the regulatory mechanisms of RNA editing in both normal hematopoiesis and hematologic malignancies. We then speculate on how targeting ADAR expression and site-specific RNA substrates might serve as a therapeutic avenue for affected patients.