Mitochondrial Dysfunction in Normal and Malignant Hematopoiesis

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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 genes related to the mitochondrial unfolded protein response (mtUPR). Thus, increased ClpP may be a marker of increased mitochondrial stress in a subset of AML patients and a common event downstream of multiple genetic mutations. Mechanistically, we discovered that ClpP functions to maintain the integrity of the respiratory chain by degrading excess and misfolded respiratory chain complex proteins. Chemical or genetic inhibition of ClpP in AML impairs respiratory chain activity and increases reactive oxygen species generation. Inhibiting ClpP preferentially kills AML cells and stem cells with high ClpP expression. In contrast, AML cells with low ClpP levels and normal hematopoietic cells are resistant. Thus, ClpP may represent a new therapeutic target for AML and we are currently developing selective and potent ClpP inhibitors.Our shRNA screen for new AML targets also identified the mitochondrial protease NLN (Neurolysin), that has an ill-defined function in the mitochondrial. In unpublished data, we showed that NLN is upregulated in a subset of AML cells. We discovered that NLN promotes the assembly of respiratory chain supercomplexes. Respiratory chain supercomplexes are higher order structures of the respiratory chain that maintain efficient oxidative metabolism and the integrity of the mitochondria. We showed that genetic or chemical inhibition of NLN impairs respiratory chain supercomplex formation, decreases oxidative metabolism, and reduces the growth and viability of AML cells.In summary, AML cells have a unique reliance on mitochondrial pathways for energy production as well as maintaining stemness. Targeting these mitochondrial vulnerabilities could represent new therapeutic strategies for this hematologic malignancy. DisclosuresSchimmer:Otsuka Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medivir AB: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.