The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage

Cancer cells are metabolically similar to their corresponding normal tissues. Differences between cancers and normal tissues may reflect reprogramming during transformation or maintenance of the metabolism of the specific normal cell type that originated the cancer. Here, we compare glucose metabolism in hematopoiesis and leukemia. Thymus T cell progenitors were glucose avid and oxidized more glucose in the tricarboxylic acid cycle through pyruvate dehydrogenase (PDH) as compared with other hematopoietic cells. PDH deletion decreased double-positive T cell progenitor cells but had no effect on hematopoietic stem cells, myeloid progenitors, or other hematopoietic cells. PDH deletion blocked the development of Pten-deficient T cell leukemia, but not the development of a Pten-deficient myeloid neoplasm. Therefore, the requirement for PDH in leukemia reflected the metabolism of the normal cell of origin independently of the driver genetic lesion. PDH was required to prevent pyruvate accumulation and maintain glutathione levels and redox homeostasis.

Automated summary

Cancer cells have metabolic similarities with normal tissues, but differences may be due to reprogramming during transformation or maintenance of specific cell type metabolism. This study compared glucose metabolism in hematopoiesis and leukemia, finding that PDH deletion affects the development of T cell leukemia but not myeloid neoplasms, emphasizing the role of PDH in maintaining normal cell metabolism in leukemia.