Inhibition of cGAS as a novel treatment for acute myeloid leukemia 9292

Abstract Description Acute myeloid leukemia (AML) is an aggressive blood cancer featuring clonal expansion of malignant myeloid progenitors. Current treatment of AML remains a combination of cytarabine and anthracycline that causes dsDNA breaks. Although this regimen initially reduces leukemic cells, almost 65% of patients suffer a relapse. Thus, a better understanding of the molecular pathogenesis of AML is needed to devise more effective therapeutic strategies. cGAS functions in immune responses by sensing double-stranded DNA or mitochondrial DNA in the cytosol of a damaged cell. cGAS binding to such DNA triggers a cell cycle-dependent response in which “Stimulator of Interferon Genes” (STING) mediates the expression of inflammatory genes, including IFN-1, IL6 and TNFα. Hematopoietic stem cells in this inflammatory environment are biased to undergo myeloid differentiation. Our preliminary data indicating that, in an adoptive transfer mouse model of AML, animals that received cGAS-/-AML cells didn’t develop full leukemia even at 1yr post-transplant. Thus, leukemic cells may need cell-autonomous cGAS to expand, and cGAS may be pro-tumorigenic in AML. Moreover, mRNA levels of cGAS, STING, IL-6 and TNFα are altered in samples from AML patients, suggesting cGAS-related inflammation may be persistent in human leukemias.Indeed, most AML cells exhibit elevated DNA damage or mutations, which could lead to ds/mt DNA release and excessive cGAS activation. cGAS may be a novel therapeutic target for AML. Funding Sources Pre-clinical AstraZeneca Grant Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)