ADAR1 is required for hematopoietic progenitor cell survival via RNA editing

Adenosine Deaminase Acting on RNA 1 (ADAR1) is an RNA-editing enzyme that converts adenosine to inosine, following RNA transcription. ADAR1's essential role in embryonic development, especially within the hematopoietic lineage, has been demonstrated in knockout mice. However, a specific role for ADAR1 in adult hematopoietic progenitor cells (HPCs) remains elusive. In this report, we show that ADAR1 is required for survival of differentiating HPCs as opposed to more primitive cells in adult mice by multiple strategies targeting floxed ADAR1 for deletion by Cre recombinase. As a consequence, ADAR1-deficient hematopoietic stem cells (HSCs) were incapable of reconstituting irradiated recipients although being phenotypically present in the recipient bone marrow. While an effect on HSCs cannot be completely ruled out, the preferential effect of ADAR1 absence on HPCs over more primitive hematopoietic cells was consistent with the increased expression of ADAR1 within HPCs, as well as the inability of ADAR1-deficient HPCs to form differentiated colonies and increased apoptotic fraction during ex vivo culture. Moreover, we have obtained direct evidence that ADAR1 functions in HPCs via an RNA-editing dependent mechanism. Therefore, ADAR1 plays an essential role in adult hematopoiesis through its RNA editing activity in HPCs.