Defining Leukemia Stem Cells in Acute Lymphoblastic Leukemia

Since their discovery, leukemia stem cells (LSCs) have been an intensive focus of investigation, particularly in acute myeloid leukemia(AML), with the development of several new LSC-targeting therapies currently in clinical trials for AML. Preliminary studies from our group and others indicate that ALL LSCs are heterogeneous with respect to their differentiation states, suggesting that they may be difficult to target therapeutically. Moreover, in our preliminary studies, we find that ALL LSCs are plastic they are present in multiple lymphoid progenitor-like states, and LSCs from each state can reconstitute the entire cellular diversity of ALL. Using primary human patient ALLcells and patient-derived xenografts (PDXs), we find that as the most differentiated LSCs upwardly reconstitute ALL upon xenotransplantation, they engage oxidative metabolic pathways. This objective of this proposal is to perform the preclinical studies necessary to determine whether targeting mechanisms regulating ALL LSC plasticity represents a viable approach to therapy. In this proposal, we aim to test our hypothesis that ALL LSCs alter their metabolic activity to regulate cellular plasticity