A-To-I Rna Deaminase Deregulation In Pre-Leukemia Stem Cell Evolution

While inflammation induced ADAR1 RNA deaminases protect the human genome from retroviral integration, deregulation promotes therapeutic resistance in many malignancies. However, the combinatorial role of these deaminases in pre-leukemia stem cell (pre-LSC) evolution to therapy resistant LSC had not been elucidated. Thus, we performed whole genome sequencing (WGS) analysis of 43 CD34+pre-leukemic myeloproliferative neoplasm (MPN) samples compared with matched saliva and non-MPN controls andwhole transcriptome sequencing (RNA-seq) analysis of 113 FACS-purified hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) from MPN, acute myeloid leukemia (AML) and healthy young and aged samples. During MPN progression, inflammation-driven ADAR1 isoform p150 upregulation corresponded with increased Adenosine-to-Inosine (A-to-I) transitions in both MPN stem and progenitor populations. We identified unique A-to-I editing events in coding regions that are associated with either normal stem progenitors or with MPN progenitors. In addition, STAT3 transcript hyper-editing leads to STAT3beta splice isoform expression. Moreover, lentiviral ADAR1p150 overexpression enhanced replating as well as beta-catenin activation, which was reversed by lentiviral shRNA ADAR1 knockdown. In summary, innate immune deaminase deregulation fuels pre-LSC evolution to LSC and may represent a vital LSC therapeutic vulnerability. Citation Format: Qingfei Jiang, Frida Holm, Jane Isquith, Adam Mark, Cayla Mason, Eduardo Reynoso, Isabella Morris, Wenxue Ma, Raymond Diep, Jessica Pham, Chanond Nasamran, Guorong Xu, Roman Sasik, Sara Brin Rosenthal, Amanda Birmingham, Leslie Crews, Gabriel Pineda, Thomas Whisenant, Kathleen Fisch, Catriona Jamieson. A-to-I RNA deaminase deregulation in pre-leukemia stem cell evolution [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5726.