Cell-State-Specific Metabolic Dependency in Hematopoiesis and Leukemogenesis
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Cell-state-specific.pdf
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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.
Date Issued
September 2014
Journal
Cell
Publisher
Elsevier
Citation
Wang, Ying-Hua et al. “Cell-State-Specific Metabolic Dependency in Hematopoiesis and Leukemogenesis.” Cell 158.6 (2014): 1309–1323.
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.cell.2014.07.048
