ATG7 regulates energy metabolism, differentiation and survival of Philadelphia chromosome-positive cells

Maria Karvela , Pablo Baquero , Elodie M. Kuntz , Arunima Mukhopadhyay, Rebecca Mitchell, Elaine K. Allan, Edmond Chan, Kamil R. Kranc, Bruno Calabretta , Paolo Salomoni , Eyal Gottlieb, Tessa L. Holyoake , G. Vignir Helgason

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Abstract

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 towards 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.
Original languageEnglish
JournalAutophagy
Early online date11 May 2016
DOIs
Publication statusE-pub ahead of print - 11 May 2016

Keywords

  • tyrosine kinase inhibitor
  • chronic myeloid leukemia
  • ATG7

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    Karvela , M., Baquero , P., Kuntz , E. M., Mukhopadhyay, A., Mitchell, R., Allan, E. K., ... Vignir Helgason, G. (2016). ATG7 regulates energy metabolism, differentiation and survival of Philadelphia chromosome-positive cells. Autophagy. https://doi.org/10.1080/15548627.2016.1162359