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.
Project Goal: 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.
Project Update 2024: We have worked to understand how T-ALL cells metabolize glucose compared to normal thymocytes, and other normal blood-forming cells, such as blood stem cells. We found that T-ALL cells use more glucose than myeloid leukemia cells or most normal blood-forming cells and oxidize it in the mitochondria. Blocking glucose oxidation stopped the development of T-ALL. Blocking glucose oxidation also reduced the growth of normal double positive T cell progenitor cells in the thymus. Unlike T-ALL cells, blood-forming stem cells in the bone marrow as well as most other blood-forming cells in the bone marrow, and myeloid leukemia cells, were unaffected when glucose oxidation was blocked. Work on cancer metabolism suggests that the special metabolic features of cancer cells are caused by the mutations present in those cells. However, our work suggested that the metabolic requirements of leukemia cells mirror those of the normal cell type that the leukemia originated from, independently of the mutation that produced the cancer. Our subsequent work has focused on understanding why T-ALL needs to oxidize glucose but other blood-forming cells do not. We performed metabolic analysis in T-ALL cells and normal thymocytes which have impaired glucose oxidation in order to understand this. We found many metabolic disturbances after blocking glucose oxidation including in unexpected pathways. We have followed up several on them and have found that additional metabolic pathways whose disruption stops leukemia from developing. Our work suggests that intervention in the form of targeting glutathione or glucose oxidation metabolism can be a way to stop T-ALL development. We are continuing to investigate the role of these pathways in leukemia development, focusing on the role of glutathione in T-ALL and acute myeloid leukemia (AML).
