DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted October 28, 2016
Catriona Jamieson, M.D., Ph.D., University of California in San Diego
Leslie Crews, Ph.D., University of California, San Diego
Edward Ball, M.D., University of California, San Diego
Anna Kulidjian, M.D., University of California, San Diego
Rainer Storb, M.D., Fred Hutchinson Cancer Research Center

Identification of Novel RNA Editing Biomarkers of Human Leukemia Stem Cell Generation
Catriona Jamieson, M.D., Ph.D., University of California in San Diego

Catriona Jamieson, M.D., Ph.D.
University of California in San Diego

Military personnel are often exposed to toxic environmental substances, including viral pathogens that may increase their risk for developing cancer. Inflammation caused by viral insult is a normal immunological response. Dr. Catriona Jamieson from the University of California in San Diego, with support from an FY13 Idea Award with Special Focus, sought to investigate the role of inflammation associated with a viral infection that can lead to the generation of leukemia stem cells (LSCs) and ultimately the progression to acute myeloid leukemia (AML). Recent reports have demonstrated that activation of RNA editing of molecular pathways during an inflammatory response is associated with the generation of LSCs in leukemia. The molecular evolution of LSCs has also been linked to therapeutic resistance in AML. Dr. Jamieson aimed to identify novel RNA biomarkers and inflammation-associated molecular mechanisms that predict increased risk for the development of therapy-resistant leukemia using a cohort of military personnel for the study.

Dr. Jamieson and her team have uncovered the signaling mechanisms behind the role of adenosine deaminase associated with RNA 1 (ADAR1) in progression to leukemia. ADAR1 is an inflammation-responsive RNA editing enzyme involved in self-renewal and survival gene transcription that has been shown to maintain therapy-resistant LSCs. Dr. Jamieson's studies have detected unique antiviral gene expression signatures that distinguish LSC from normal hematopoietic progenitors. Ongoing studies aim to determine if this antiviral gene expression signature is present more frequently in virally exposed individuals. Individuals with the identified gene expression signature were shown to have hyper-activated ADAR1 in therapy-resistant LSC in response to an inflammatory insult. This hyper-ADAR1 activity blocks the microRNA Let-7, which functions as a gatekeeper in the control of cellular self-renewal in blood cells, ultimately resulting in the progression of leukemia via the production of LSCs. Dr. Jamieson also demonstrated that targeting of ADAR1 with small molecules such as inhibitors of the pro-inflammatory JAK/STAT pathway can reduce ADAR1's effect on LSC self-renewal.

In addition, in a related comparative whole transcriptome sequencing study carried out in collaboration with clinicians Dr. Edward Ball and Dr. Anna Kulidjian also at the University of California in San Diego, and Dr. Rainer Storb of the Fred Hutchinson Cancer Research Center, Dr. Jamieson's team found that LSCs purified from AML patient samples harbored widespread disruption of RNA splicing factor expression, which was associated with characteristic pro-inflammatory gene expression profiles. RNA editing activity can influence RNA splicing outcomes, and together these pathways represent novel sources of LSC-specific neoantigen generation and potential therapeutic targets for leukemia. These studies represent an important advancement in the understanding of the molecular mechanisms of viral infection, inflammation, LSC generation, and malignant reprogramming. Leukemia patients with hyperactive ADAR1 may benefit from therapeutic targeting of ADAR1 by increasing levels of the microRNA Let-7, leading to the reduction of LSC generation to prevent cancer progression and resistance to therapeutic interventions.

Publications:

Zipeto MA, Court AC, Sadarangani A, Delos Santos NP, Balaian L, Chun HJ, Pineda G, Morris SR, Mason CN, Geron I, Barrett C, Goff DJ, Wall R, Pellecchia M, Minden M, Frazer KA, Marra MA, Crews LA, Jiang Q, Jamieson CH. ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis Cell Stem Cell. 2016 Aug 4;19(2):177-91
Crews LA, Balaian L, Leu H, Delos Santos N, Court AC, Lazzari E, Sadarangani A, Zipeto MA, La Clair JJ, Villa R, Morris SR, Storb R, Kulidjian AA, Ball ED, Burkart MD, & Jamieson CH. RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML. Cell Stem Cell 2016;19:1-14.

Press Release:

https://health.ucsd.edu/news/releases/Pages/2016-06-09-gene-editing-system-generates-leukemia-stem-cells.aspx

Link:

Public and Technical Abstracts: Identification of Novel RNA Editing Biomarkers of Human Leukemia Stem Cell Generation

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Last updated Friday, October 28, 2016