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Cell DOI:10.1016/j.cell.2014.07.048

Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis.

Publication TypeJournal Article
Year of Publication2014
AuthorsWang, Y-H, Israelsen, WJ, Lee, D, Yu, VWC, Jeanson, NT, Clish, CB, Cantley, LC, Heiden, MGVander, Scadden, DT
JournalCell
Volume158
Issue6
Pages1309-23
Date Published2014 Sep 11
ISSN1097-4172
KeywordsAnimals, Gene Deletion, Glycolysis, Hematopoiesis, Hematopoietic Stem Cells, Humans, Isoenzymes, L-Lactate Dehydrogenase, Leukemia, Mice, Mice, Congenic, Mice, Inbred C57BL, Pyruvate Kinase
Abstract

The balance between oxidative and nonoxidative 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 a deficiency in the M2 pyruvate kinase isoform (PKM2) reduces the levels of metabolic intermediates important for biosynthesis and impairs progenitor function without perturbing hematopoietic stem cells (HSCs), whereas lactate dehydrogenase A (LDHA) deletion significantly inhibits the function of both HSCs and progenitors during hematopoiesis. In contrast, leukemia initiation by transforming alleles putatively affecting either HSCs 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 explored therapeutically for treating leukemia while preserving HSC function.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01038-1
DOI10.1016/j.cell.2014.07.048
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25215489?dopt=Abstract

Alternate JournalCell
PubMed ID25215489
PubMed Central IDPMC4197056
Grant ListU54 CA163191 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
R01 HL044851 / HL / NHLBI NIH HHS / United States
T32 HL087735 / HL / NHLBI NIH HHS / United States
5T32HL87735-4 / HL / NHLBI NIH HHS / United States
R01 CA168653 / CA / NCI NIH HHS / United States
HL044851 / HL / NHLBI NIH HHS / United States
C06 CA059267 / CA / NCI NIH HHS / United States
CA148180 / CA / NCI NIH HHS / United States
R01CA168653 / CA / NCI NIH HHS / United States
P30CA147882 / CA / NCI NIH HHS / United States
R01 DK050234 / DK / NIDDK NIH HHS / United States
P30 CA147882 / CA / NCI NIH HHS / United States
DK050234 / DK / NIDDK NIH HHS / United States