Summary This proposal is focused on the development of improved therapies for acute myeloid leukemia (AML). The central premise of our all our work is that AML is driven by a biologically distinct leukemia stem cell (LSC) population. While the conceptual importance of targeting leukemic disease at its root is clear, studies in recent years have demonstrated that the inherent intra-patient heterogeneity of LSC populations makes complete eradication a very challenging objective for most patients. Our studies have therefore attempted to identify common foundational properties of primary human LSCs that can employed in the development of therapeutic strategies in the hope that intrinsic heterogeneity can be overcome. Of particular interest, we have described distinct metabolic properties in LSCs, that provide new opportunities for intervention. Specifically, inhibition of BCL2 acts to inhibit oxidative phosphorylation in LSCs, resulting in selective eradication of the LSC population. Recent translation of this observation to clinical studies has demonstrated strong efficacy for newly diagnosed AML patients, and appears to be on the verge of altering the current standard of care. Despite these exciting advances though, relapse remains common and further elucidation of LSC properties is essential. To this end, we have recently begun to describe the mechanisms that drive relapse of AML patients following treatment with a BCL2 inhibitor. These studies have identified entirely unexpected and new aspects of LSC biology that have important ramifications for our basic understanding of AML, as well as the design of improved therapeutic regimens. Specifically, we have demonstrated that at least two distinct LSC populations can co-exist in the same patient. The genetic, epigenetic, and metabolic properties of co-resident LSC subpopulations can vary, giving rise to differing levels of drug responsiveness. The focus of our studies going forward will be to understand and exploit these findings towards the goal of improved outcomes for AML patients.

R35CA242376

2020-09-08

2027-08-31