Journal
AUTOPHAGY
Volume 12, Issue 6, Pages 936-948Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2016.1162359
Keywords
ATG7; autophagy; chronic myeloid leukemia; energy metabolism; erythroid differentiation; glycolysis; oxidative phosphorylation; reactive oxygen species; tyrosine kinase inhibitor
Categories
Funding
- Medical Research Council [G0600782, G0900882]
- Medical Research Council (CHOICES)
- Medical Research Council (ISCRTN) [61568166]
- Kay Kendall Leukemia Fund [KKL404, KKL501]
- Glasgow Experimental Cancer Medicine Center
- Cancer Research UK
- Chief Scientist's Office (Scotland)
- Scottish Universities Life Science Alliance [MSD23_G_Holyoake-Chan]
- Scottish National Blood Transfusion Service
- Cancer Research UK program [C11074/A11008]
- NCI [CA95111]
- Brain Tumor Charity
- Association for Internal Cancer Research
- National Institute for Health Research University College London Hospitals Biomedical Research Center
- Cancer Research UK [18278, 11008, 14633] Funding Source: researchfish
- MRC [G0900882, G0600782] Funding Source: UKRI
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A major drawback of tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) is that primitive CML cells are able to survive TKI-mediated BCR-ABL inhibition, leading to disease persistence in patients. Investigation of strategies aiming to inhibit alternative survival pathways in CML is therefore critical. We have previously shown that a nonspecific pharmacological inhibition of autophagy potentiates TKI-induced death in Philadelphia chromosome-positive cells. Here we provide further understanding of how specific and pharmacological autophagy inhibition affects nonmitochondrial and mitochondrial energy metabolism and reactive oxygen species (ROS)-mediated differentiation of CML cells and highlight ATG7 (a critical component of the LC3 conjugation system) as a potential specific therapeutic target. By combining extra-and intracellular steady state metabolite measurements by liquid chromatography-mass spectrometry with metabolic flux assays using labeled glucose and functional assays, we demonstrate that knockdown of ATG7 results in decreased glycolysis and increased flux of labeled carbons through the mitochondrial tricarboxylic acid cycle. This leads to increased oxidative phosphorylation and mitochondrial ROS accumulation. Furthermore, following ROS accumulation, CML cells, including primary CML CD34(+) progenitor cells, differentiate toward the erythroid lineage. Finally, ATG7 knockdown sensitizes CML progenitor cells to TKI-induced death, without affecting survival of normal cells, suggesting that specific inhibitors of ATG7 in combination with TKI would provide a novel therapeutic approach for CML patients exhibiting persistent disease.
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