Identification of Novel RNA Editing Biomarkers of Human Leukemia Stem Cell Generation

Principal Investigator: JAMIESON, CATRIONA
Program: PRCRP
Proposal Number: CA130445
Award Number: W81XWH-14-1-0121
Funding Mechanism: Idea Award with Special Focus
Partnering Awards:
Award Amount: $465,000.00


While chemical agents and radiation have been linked to the development of some blood cancers, recent studies suggest that innate immune and inflammatory responses triggered by military zone environmental contaminants, such as benzene, or emerging viral pathogens, may enhance severity of hematological malignancies. Because primate-specific RNA editing can be increased in response to benzene and virally elicited inflammatory mediator production, we have focused on the role of an inflammation-responsive stem cell self-renewal and RNA editing gene, adenosine deaminase associated with RNA (ADAR1), in leukemia stem cell generation and therapeutic resistance. Prior to the advent of next-generation bulk population and single-cell sequencing technologies, it was difficult to detect RNA processing changes or pathogen-derived sequences in rare cancer stem cell populations. Recent advances in DNA and RNA sequencing technologies have provided important molecular insights into genetic and epigenetic mechanisms of disease pathogenesis. The proposed research is highly innovative because we aim to identify, at the bulk population and single-cell level, novel RNA editing biomarkers of blood cancer development due to exposure to service-connected environmental exposures and to investigate a potential viral pathogenic origin for therapeutically resistant leukemia stem cells in myeloid and lymphoid leukemias in military versus civilian patient populations compared with healthy individuals. We expect that this research will lead to the rapid development of clinical diagnostic tests detecting abnormal inflammatory, anti-viral and RNA editing biomarkers within 2-5 years. Therapeutic strategies targeting these novel leukemia stem cell regulatory pathways could be in preclinical testing within the same timeframe. The potential benefits of these clinical applications are to provide new diagnostic and prognostic tests that will improve patient stratification for clinical trials and treatment selection.

This research will provide novel insights into the pathogenesis of acute leukemia in adults in the military and veteran community in particular and to patients in the civilian population who may be at risk for exposure to similar environmental triggers as a result of localized environmental conditions. Therefore, this research will also help military/veteran and civilian populations by identifying possible ways to prevent exposure to inflammatory or viral triggers associated with the development and therapeutic resistance of acute leukemia. This research will advance cancer research and patient care for both military/veteran and civilian patients with acute leukemia, and their family members and healthcare providers, by identifying new treatment strategies for patients that often do not have many, or any, therapeutic options. Because we aim to investigate a link between viruses, inflammatory and anti-viral pathway activation, and leukemia, this will inform future prevention and personal protection measures for military personnel who are exposed to viral pathogens and toxic environmental agents. New clinically applicable therapeutic strategies or vaccines could be designed to protect against carcinogenic infectious agents in military environments as well as weaponized biological agents.