Mitochondrial Dysfunction in Normal and Malignant Hematopoiesis

AML (Acute Myeloid Leukemia) is an aggressive hematologic malignancy with a high rate of relapse. Therefore, it is important to identify novel therapeutic strategies for patients with this disease. We and others have shown that AML cells and stem cells have a unique reliance on mitochondrial oxidative metabolism and are highly vulnerable to strategies that target mitochondrial pathways. This unique vulnerability is due, at least in part, to increased flux of metabolites into the TCA (Kreb's) cycle that results in increased rates of oxidative metabolism and reduced space reserve capacity (the difference between basal and maximal respiration). As a result, even relatively small reductions in the respiratory chain activity and oxidative metabolism can impact the viability of AML cells and stem cells.In this session, we will discuss mitochondrial pathways that may be potential new therapeutic targets for AML. Recently, we conducted an shRNA screen to identify components of the mitochondrial proteome that are necessary for the growth and viability of AML cells and stem cells. From this screen, we identified the serine protease, ClpP (caseinolytic protease P) that is located in the mitochondrial matrix. Compared to normal hematopoietic cells, ClpP is increased in almost half of AML patients. Increased expression of this protease occurs across morphologic subtypes, cytogenetic risk groups, and molecular mutations. ClpP expression positively correlates with increased expression of ge...
Source: Blood - Category: Hematology Authors: Tags: Metabolism and Hematologic Malignancies Source Type: research