The role of inflammation in the regulation of immune response in acute myeloid leukemia

Project Summary/Abstract Survival outcomes of acute myeloid leukemia (AML) patients are negatively affected by high inflammation in the bone marrow compared to low inflammation patients within the same molecular subgroup. The overarching goal of our study is to delineate functionally relevant contributors to aberrant inflammation, characterize changes to the inflammatory state longitudinally during different standard-of-care treatment approaches and determine whether targeting inflammation via inhibitors that target the crucial mediators of inflammation can improve treatment response and survival. The proposal was prompted by our recent characterization of inflammation- mediated progression to AML in animal models and the notable cooperation with select mutational backgrounds to promote leukemogenesis; and our notion of distinct cellular remodeling of both leukemic cells and the microenvironment to promote inflammation. We believe that the observed strong negative treatment response and survival association that was independent from other genetic contributors provides an exciting rationale to target aberrant inflammation in AML patients in order to improve treatment response and disease progression. This goal will be achieved by two independent, but complementary Specific Aims. (1) Utilizing our large cohort of 1,600 AML patients who were molecularly and clinically characterized and have a defined inflammatory state, we will characterize those patients with the highest and the lowest inflammation and compare cell state, cell fate and immune response at the single cell level via a comprehensive multi-omic approach. (2) We will track dynamics of inflammatory, immune-regulatory and associated clonal structures during different treatments via the same multi-omic profiling with an integrated approach that first profiles longitudinally collected patient samples with select genotypes during different treatments, followed by patient derived xengraft models of the same patients that will undergo 2 different therapeutic approaches followed by serial profiling, thereby allowing for direct comparison and definitive characterization of the observed changes. Lastly, we will test the effectiveness of anti-inflammatory agents (IL-1 inhibitors) to lower inflammation and prevent the inflammation- associated bone marrow remodeling and inferior treatment response. Together, our results will, for the first time, provide critically needed information to provide a basis for targeting aberrant inflammation in AML patients.