Cellular metabolism often produces toxic molecules as an unavoidable byproduct. Buildup of such molecules can stop cellular growth and cause cell death. Because of this, cells employ dedicated mechanisms to remove toxic molecules. But it is not well understood how such mechanisms differ between normal and cancer cells. The overall goal of our proposed work is to test if leukemia cells have a high requirement for removal of endogenous toxic molecules, and if this requirement can be targeted by therapy that can selectively kill leukemia cells. Our preliminary data suggest that some T cell acute lymphoblastic leukemia (T-ALL) and myeloid leukemia (AML) cells are more reliant on pathways that de...

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Cellular metabolism often produces toxic molecules as an unavoidable byproduct. Buildup of such molecules can stop cellular growth and cause cell death. Because of this, cells employ dedicated mechanisms to remove toxic molecules. But it is not well understood how such mechanisms differ between normal and cancer cells. The overall goal of our proposed work is to test if leukemia cells have a high requirement for removal of endogenous toxic molecules, and if this requirement can be targeted by therapy that can selectively kill leukemia cells. Our preliminary data suggest that some T cell acute lymphoblastic leukemia (T-ALL) and myeloid leukemia (AML) cells are more reliant on pathways that detoxify toxic molecules as compared to normal blood-forming cells. We hypothesize that blocking such detoxification pathways provides an opportunity to target and kill leukemia cells preferentially over normal cells. To test that, we propose to use human patient-derived samples and genetically engineered mice, which develop T-ALL or AML as a result of the same mutations that cause these leukemias in human patients. We will block enzymes that are needed for detoxification pathways and test if that stops the initiation and growth of leukemias in the organism. We will use advanced techniques we established in our lab to analyze which toxic molecules are elevated in leukemia cells as compared to normal cells and measure their levels. We will establish the mechanisms by which such toxic molecules stop leukemia growth or kill leukemia cells. Our work will establish the identity of endogenous toxic molecules in leukemia cells, and the mechanisms by which leukemia cells dispose of them. Our goal is to provide new targets for therapies that kill leukemia cells without killing most normal cells.

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