Metabolic Rewiring Is Essential for AML Cell Survival to Overcome Autophagy Inhibition by Loss of ATG3.
Fatima BakerIbrahim H PolatKhalil Abou-El-ArdatIslam AlshamlehMarlyn ThoelkenDaniel HymonAndrea GubasSebastian E KoschadeJonas B VischedykManuel KaulichHarald SchwalbeShabnam ShaidChristian H BrandtsPublished in: Cancers (2021)
Autophagy is an important survival mechanism that allows recycling of nutrients and removal of damaged organelles and has been shown to contribute to the proliferation of acute myeloid leukemia (AML) cells. However, little is known about the mechanism by which autophagy- dependent AML cells can overcome dysfunctional autophagy. In our study we identified autophagy related protein 3 (ATG3) as a crucial autophagy gene for AML cell proliferation by conducting a CRISPR/Cas9 dropout screen with a library targeting around 200 autophagy-related genes. shRNA-mediated loss of ATG3 impaired autophagy function in AML cells and increased their mitochondrial activity and energy metabolism, as shown by elevated mitochondrial ROS generation and mitochondrial respiration. Using tracer-based NMR metabolomics analysis we further demonstrate that the loss of ATG3 resulted in an upregulation of glycolysis, lactate production, and oxidative phosphorylation. Additionally, loss of ATG3 strongly sensitized AML cells to the inhibition of mitochondrial metabolism. These findings highlight the metabolic vulnerabilities that AML cells acquire from autophagy inhibition and support further exploration of combination therapies targeting autophagy and mitochondrial metabolism in AML.
Keyphrases
- induced apoptosis
- acute myeloid leukemia
- endoplasmic reticulum stress
- oxidative stress
- cell death
- cell cycle arrest
- signaling pathway
- allogeneic hematopoietic stem cell transplantation
- cell proliferation
- crispr cas
- dna damage
- magnetic resonance
- risk assessment
- mass spectrometry
- gene expression
- dna methylation
- acute lymphoblastic leukemia
- poor prognosis
- genome editing
- drug delivery
- heavy metals
- single cell
- genome wide
- cancer therapy
- solid state
- cell cycle