Detection and Targeting of Enzymatic Base Editing Deregulation in Leukemia Stem Cells


IN PARTNERSHIP WITH LEUKEMIA & LYMPHOMA SOCIETY AND THE PAUL G. ALLEN FRONTIERS GROUP (2020-PRESENT)

Catriona Jamieson, MD, PhD, University of California San Diego

The central dogma of molecular biology from the mid-20th century established the paradigm that DNA is transcribed into RNA, which in turn is translated into protein to carry out the diverse functions and needs of living organisms. In its original conception, information flow was modeled as being unidirectional, meaning that changes to DNA and RNA impacted changes to protein, but not the other way around. However, it is now well appreciated that enzymes can edit specific bases in DNA and RNA under certain contexts and do indeed alter a cell’s genetic material. This pathway has emerged in many cancers as a molecular signature and a mechanism of evolving resistance to therapy. However, how the dysregulation of these enzymes contributes to acute myeloid leukemia (AML) is unclear.

Catriona Jamieson and her group are probing the role of ADAR1 and APOBEC3C, two enzymes involved in RNA and DNA editing, and how they contribute to AML progression. They are determining the functional impact of these enzymes in stem cell proliferation and survival to measure how they impact the development of disease. By examining samples from patients as well as engineered cells, they are measuring global DNA and RNA editing levels, and examining the influence of inflammatory signaling on such processes and how they contribute to AML progression. These studies will allow for a deeper understanding of the mechanisms of nucleic acid editing in AML and probe whether such enzymes represent novel targets for therapies.

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