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Targeting the mitochondrial proteasome, ClpP, in AML

Aaron David Schimmer

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Canadian Institutes of Health Research (CIHR)
The outcome for most patients with AML (acute myeloid leukemia) remains poor and new treatments for this disease are needed. Here, we propose to study the mitochondrial proteasome (ClpP) as a new therapeutic target for AML. The proteasome is like the cell's garbage disposal system. Blocking the activity of the proteasome that is located in the cell's cytoplasm with drugs such as bortezomib (Velcade) improves the outcome and survival for patients with some blood cancers. However, no prior studies have investigated targeting the mitochondrial form of the proteasome. In our preliminary data, we have demonstrated that ClpP is highly expressed in most AML cell lines and patient samples but expressed at low levels in normal blood cells. We also showed that blocking ClpP using genetic or small drug-like compounds preferentially killed leukemia cells over normal cells. Here, we will determine the impact of ClpP on mitochondrial function. We will also determine why inhibition of ClpP kills leukemia cells. Finally, we will test the efficacy and toxicity of inhibiting ClpP in our mouse models of leukemia.

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