Introduction
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm initiated in hematopoietic stem cells by expression of the BCR-ABL1 fusion oncogene and its protein product, which enhances ABL1 kinase activity. Targeted BCR-ABL tyrosine kinase inhibitors (TKIs), such as Imatinib, and the second generation TKIs like Nilotinib as well as the dual specific SCR and ABL inhibitor Dasatinib have significantly slowed disease progression by eradicating the bulk of BCR-ABL1 expressing cells in the circulation. However, progression to a therapeutically resistant blast crisis (BC) phase is driven by CD34+CD38+Lin- progenitors that co-opt stem cell properties, such as enhanced self-renewal and survival, albeit in a deregulated manner. These leukemia stem cells (BC LSC) harbor altered BCL2, CD44 and beta-catenin splice isoform expression, in some cases as a result of RNA editing driven alternative splice isoform generation. We investigated the role of primate specific RNA editing in malignant reprogramming of progenitors in CML during blast crisis transformation. Whole transcriptome RNA sequencing revealed that progression from chronic phase to blast crisis was associated with increased RNA editing driven by adenosine deaminase associated with RNA (ADAR1), an RNA editase that converts adenosines to inosines which are subsequently read as guanosine bases in RNA usually within the context of a hairpin loop formed by primate specific Alu sequences. Lentivirally enforced ADAR1 overexpression increased myeloid progenitor expansion and ADAR1 knockdown reduced serial transplantation potential of blast crisis progenitors suggesting that ADAR1 plays a critical role in malignant reprogramming by endowing progenitors with self-renewal potential. Current efforts focus on early detection of RNA editing using an ADAR-luciferase reporter assay as well as targeted small molecule-mediated ADAR1 inhibition to prevent malignant reprogramming.