Fine-tuning metabolism | Nature Reviews Cancer

Access through your institution Buy or subscribe The authors first looked at PK and found that BM cells predominantly expressed the M2 isoform (PKM2), which promotes glycolysis, and not

PKM1, which promotes oxidative phosphorylation. Deletion of PKM2 in BM cells in adult mice had no effect on the maintenance of normal haematopoiesis. However, under stress conditions (tested

through competitive BM repopulation assays using a mixture of PKM2-null and wild-type cells), progenitor cells (but not long-term HSCs) lacking PKM2 had a reduced ability to reconstitute

mature blood cells. Haematopoietic progenitor cells lacking PKM2 had increased oxidative metabolism, indicated by an increased oxidative state, increased mitochondrial membrane potential and

decreased lactate production. The authors also showed that cells that lacked PKM2 then expressed PKM1; as PKM1 promotes oxidative phosphorylation, this is consistent with the metabolic

changes observed in these cells. LDH converts pyruvate into lactate and is also crucial for glycolysis. BM cells predominantly express the LDHA isoform, so the authors conditionally knocked

out LDHA in mouse BM cells. Similar to progenitor cells lacking PKM2, progenitor cells lacking LDHA had defects in BM repopulation, but in contrast to the results with PKM2, LDHA loss

reduced the repopulating ability of HSCs as well. Oxidative state and mitochondrial membrane potential were also increased in LDHA-null cells. However, these cells had increased levels of

reactive oxygen species (ROS), which was not observed in cells lacking PKM2, and several lines of evidence indicated that the increased ROS were at least partially responsible for the

effects of LDHA loss on HSCs. This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print

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local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support REFERENCES * Wang,

Y. H. et al. Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. _Cell_ 158, 1309–1323 (2014) Article  CAS  Google Scholar  Download references Authors * Sarah

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Seton-Rogers, S. Fine-tuning metabolism. _Nat Rev Cancer_ 14, 705 (2014). https://doi.org/10.1038/nrc3839 Download citation * Published: 06 October 2014 * Issue Date: November 2014 * DOI:

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