Cell-State-Specific Metabolic Dependency in Hematopoiesis and Leukemogenesis
Author(s)Wang, Ying-Hua; Lee, Dongjun; Yu, Vionnie W.C.; Jeanson, Nathaniel T.; Clish, Clary B.; Cantley, Lewis C.; Scadden, David T.; Israelsen, William James; Vander Heiden, Matthew G.; ... Show more Show less
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The balance between oxidative and non-oxidative glucose metabolism is essential for a number of pathophysiological processes. By deleting enzymes that affect aerobic glycolysis with different potencies, we examine how modulating glucose metabolism specifically affects hematopoietic and leukemic cell populations. We find that deficiency in the M2 pyruvate kinase isoform (PKM2) reduces levels of metabolic intermediates important for biosynthesis and impairs progenitor function without perturbing hematopoietic stem cells (HSC), whereas lactate dehydrogenase-A (LDHA) deletion significantly inhibits the function of both HSC and progenitors during hematopoiesis. In contrast, leukemia initiation by transforming alleles putatively affecting either HSC or progenitors is inhibited in the absence of either PKM2 or LDHA, indicating that the cell state-specific responses to metabolic manipulation in hematopoiesis do not apply to the setting of leukemia. This finding suggests that fine-tuning the level of glycolysis may be therapeutically explored for treating leukemia while preserving HSC function.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology
Wang, Ying-Hua et al. “Cell-State-Specific Metabolic Dependency in Hematopoiesis and Leukemogenesis.” Cell 158.6 (2014): 1309–1323.
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