Pyruvate kinase M2 plays distinct roles in hematopoietic stem cells and leukemia (111.19)

It has been realized that different cell states employ different metabolic modes. Whether metabolism is a determinant of cell state is unclear, but studies in cancer suggest that altering metabolic activity can modify cellular function. Cancer cells metabolize glucose through glycolysis even in the presence of oxygen, a phenomenon called Warburg effect. Normal somatic cells thought to also preferentially use glycolytic metabolism are tissue stem cells, particularly the hematopoietic stem cells (HSC) resident in the hypoxic microenvironment of the bone marrow. Recently the molecular basis for Warburg effect in cancer cells has been identified as due to a specific isoform of pyruvate kinase M2 (PKM2). Interestingly, HSC also express PKM2. Using a mouse strain that allows conditional deletion of PKM2, we observed that PKM2 depletion enhances normal HSC function as revealed by a competitive transplantation assay. The altered cellular function is accompanied with decreased glycolysis and increased oxidative phosphorylation specifically in the primitive stem/progenitor cell population. Notably however, PKM2 deletion markedly disadvantages disease development in mouse models of both acute and chronic myeloid leukemia. Such a distinction in response between normal and malignant cells is unprecedented to our knowledge and may offer a highly unique opportunity to advantage normal while disadvantaging malignant cells of the hematopoietic lineage by targeting a single metabolic enzyme.