Effects of Hypomethylating Agents on Gene Modulation in the Leukemic Microenvironment and Disease Trajectory in a Mouse Model of AML

Abstract

Hypomethylating agents (HMAs), such as decitabine and 5-azacytidine (AZA), are valuable treatment options for patients with acute myeloid leukemia that are ineligible for intensive chemotherapy. Despite providing significant extensions in survival when used alone or in combination, eventual relapse and resistance to HMAs are observed. The mechanisms leading to these outcomes are still not well defined and may, in part, be due to a focus on leukemic populations with limited information on the effects of HMAs on non-leukemic cells in the blood and other tissue compartments. In this study, we elucidated effects on immune-related gene expression in non-leukemic blood cells and the spleen during AZA treatment in leukemia-challenged mice. We observed significant changes in pathways regulating adhesion, thrombosis, and angiogenesis as well as a dichotomy in extramedullary disease sites that manifests during relapse. We also identify several genes that may contribute to the anti-leukemic activity of AZA in blood and spleen. Overall, this work has identified novel gene targets and pathways that could be further modulated to augment efficacy of HMA treatment.