Abstract 247: ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. While DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity may also be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, whole transcriptome sequencing of normal, chronic phase (CP) and serially transplantable blast crisis (BC) chronic myeloid leukemia (CML) progenitors revealed increased interferon-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the interferon responsive ADAR1 p150 isoform and a propensity for increased A-to-I RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promoted expression of the myeloid transcription factor PU.1 and induced malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a mis-spliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of BC CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies. Citation Format: Qingfei Jiang, Leslie A. Crews, Christian L. Barrett, Angela Court-Recart, Daniel Goff, Anil Sadarangani, Jessica Rusert, Sheldon Morris, Lawrence Goldstein, Hye-Jung Chun, Marco Marra, Kelly Fraser, Kim-Hien Dao, Mark Minden, Catriona Jamieson. ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 247. doi:10.1158/1538-7445.AM2013-247