Title: Characterization of the Role of ADAR1 in Oncogenic Transformation of Progenitors Project Summary Our overall goal is to define the role of ADAR1 in the oncogenic transformation of pre-leukemic progenitors in myeloproliferative neoplasms (MPNs) into self-renewing leukemia stem cells (LSCs). Recent research suggests that ADAR1-mediated RNA editing is an essential driver of human cancer progression. Though many RNA editing sites have been identified, the functional relevance of ADAR1-mediated RNA editing, especially in primary patient samples, is still unresolved. This study represents a unique opportunity to understand the consequences of malignant RNA editing in cancer stem cells that drive cancer progression and therapeutic resistance. Inflammatory cytokine driven activation of ADAR1 has been implicated in malignant reprogramming of progenitors into self-renewing cancer stem cells in a broad array of malignancies. Previously, we showed that ADAR1 enhances self-renewal of pre-leukemic progenitors in chronic myeloid leukemia (CML), in part as a result of A-to-I editing induced missplicing of GSK3?, which prevents degradation of the self-renewal agonist, ?-catenin. More recently, ADAR1 has been shown to play a role in microRNA biogenesis and specifically impairs let-7 family microRNA production. Notably, ADAR1 is also upregulated during progression from myelofibrosis (MF) to secondary acute myeloid leukemia (sAML). In this grant, we will first examine if ADAR1-mediated RNA editing can alter self-renewal capacity, survival, and cell cycle in primary patient progenitors and normal progenitors following lentiviral transduction with MPN oncogenes. Given that >90% of A-to-I editing events occur in the context of primate-specific Alu elements, the necessity of Alu sequences for ADAR1 function will be assessed using both human and mouse progenitors. Secondly, the impact of RNA editing on let-7 microRNA biogenesis and degradation will be determined. Lastly, we discovered that ADAR1 edits APOBEC3 cytidine deaminase, which introduces C-to-T mutations in a broad array of malignancies. Moreover, multiple A-to-I editing sites occur in intronic, exonic, as well as protein coding regions of APOBEC3D and 3G, suggesting that ADAR1 might regulate APOBEC expression and protein function. Thus, we aim to decipher the role of ADAR1 in deregulation of APOBEC3s and introduction of DNA hypermutation patterns during evolution of pre-leukemic progenitors into leukemia stem cells. In addition to vastly expanding our knowledge of A-to-I editing function in progenitor cell maintenance, this research program will inform the development of malignant ADAR1 editase detection and inhibition strategies that may help to prevent progression of MPNs to acute myeloid leukemia.
Leukemia stem cell (LSC)-driven myeloproliferative neoplasm (MPN) progression to acute leukemia remains a major cause of morbidity and mortality. Because adenosine deaminase associated with RNA1 (ADAR1) promotes cancer progression, we will investigate ADAR1's role in LSC generation. Discoveries made in the context of this proposal, will accelerate development of more effective clinical strategies aimed at predicting and preventing cancer progression, which remains the leading cause of cancer-related mortality.
|Lazzari, Elisa; Mondala, Phoebe K; Santos, Nathaniel Delos et al. (2017) Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma. Nat Commun 8:1922|
|Jiang, Qingfei; Crews, Leslie A; Holm, Frida et al. (2017) RNA editing-dependent epitranscriptome diversity in cancer stem cells. Nat Rev Cancer 17:381-392|