The Role of Pyruvate Dehydrogenase in Leukemia
Different cancers start from different types of normal stem and progenitor cells in tissues. This raises the possibility that the molecular makeup of cancers, and how vulnerable they are to therapies, is to some extent inherited from their cell types of origin. We recently developed a new technique that can measure the small molecules of cellular metabolism in rare cell types isolated from tissues. This allows us to compare the metabolism of cancer cells with the metabolism of their normal cells of origin.
We now propose to use this technique in blood-forming stem and progenitor cells and the leukemias they produce. In initial work, we have found that the break-down of glucose using oxygen is required in one type of T cell leukemia common in children, but not in myeloid leukemia. This metabolic requirement is inherited from the specific cell type that originates the cancer. It is not shared by most normal blood-forming stem and progenitor cells. Targeting this requirement may kill T cell leukemia without harming most normal cells. We will investigate why this key metabolic pathway is used in T cell leukemia but not myeloid leukemia. We will test if drugs that block this pathway can stop the growth of human and murine model T cell leukemias in vivo. Many current therapies for pediatric T cell leukemia are limited by toxicity to normal stem and progenitor cells. Our goal is to find metabolic targets for drugs that will kill leukemia cells, but spare most normal cells.