Journal
BLOOD
Volume 125, Issue 13, Pages 2120-2130Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-08-594408
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Funding
- Canadian Stem Cell Network
- Leukemia and Lymphoma Society
- National Institutes of Health (National Cancer Institute) [1R01CA157456]
- Ontario Ministry of Research and Innovation
- Princess Margaret Hospital Foundation
- Ministry of Long Term Health and Planning in the Province of Ontario
- Barbara Baker chair in Leukemia and Related Diseases
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Mitochondrial respiration is a crucial component of cellular metabolismthat can become dysregulated in cancer. Compared with normal hematopoietic cells, acute myeloid leukemia (AML) cells and patient samples have higher mitochondrial mass, without a concomitant increase in respiratory chain complex activity. Hence these cells have a lower spare reserve capacity in the respiratory chain and are more susceptible to oxidative stress. We therefore tested the effects of increasing the electron flux through the respiratory chain as a strategy to induce oxidative stress and cell death preferentially in AML cells. Treatment with the fatty acid palmitate induced oxidative stress and cell death in AML cells, and it suppressed tumor burden in leukemic cell lines and primary patient sample xenografts in the absence of overt toxicity to normal cells and organs. These data highlight a unique metabolic vulnerability in AML, and identify a new therapeutic strategy that targets abnormal oxidative metabolism in this malignancy.
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