Very long chain fatty acid metabolism is required in acute myeloid leukemia

Author:

Tcheng Matthew1ORCID,Roma Alessia1,Ahmed Nawaz1,Smith Richard W.2,Jayanth Preethi1,Minden Mark D.3ORCID,Schimmer Aaron D.3,Hess David A.4,Hope Kristin5,Rea Kevin A.6,Akhtar Tariq A.6ORCID,Bohrnsen Eric7,D’Alessandro Angelo7,Mohsen Al-Walid89ORCID,Vockley Jerry89ORCID,Spagnuolo Paul A.1ORCID

Affiliation:

1. Department of Food Science, University of Guelph, Guelph, ON, Canada;

2. University of Waterloo Mass Spectrometry Facility, Department of Chemistry, Waterloo, ON, Canada;

3. Princess Margaret Cancer Center, Ontario Cancer Institute, Toronto, ON, Canada;

4. University of Western Ontario, Robarts Research Institute, London, ON, Canada;

5. Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada;

6. Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada;

7. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO;

8. Department of Pediatrics and Center for Rare Disease Therapy, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA; and

9. Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA

Abstract

Abstract Acute myeloid leukemia (AML) cells have an atypical metabolic phenotype characterized by increased mitochondrial mass, as well as a greater reliance on oxidative phosphorylation and fatty acid oxidation (FAO) for survival. To exploit this altered metabolism, we assessed publicly available databases to identify FAO enzyme overexpression. Very long chain acyl-CoA dehydrogenase (VLCAD; ACADVL) was found to be overexpressed and critical to leukemia cell mitochondrial metabolism. Genetic attenuation or pharmacological inhibition of VLCAD hindered mitochondrial respiration and FAO contribution to the tricarboxylic acid cycle, resulting in decreased viability, proliferation, clonogenic growth, and AML cell engraftment. Suppression of FAO at VLCAD triggered an increase in pyruvate dehydrogenase activity that was insufficient to increase glycolysis but resulted in adenosine triphosphate depletion and AML cell death, with no effect on normal hematopoietic cells. Together, these results demonstrate the importance of VLCAD in AML cell biology and highlight a novel metabolic vulnerability for this devastating disease.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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