ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition

• Published in: Leukemia Vol. 31; no. 10; pp. 2143 - 2150
• Main Authors: Ju, H-Q, Zhan, G, Huang, A, Sun, Y, Wen, S, Yang, J, Lu, W-h, Xu, R-h, Li, J, Li, Y, Garcia-Manero, G, Huang, P, Hu, Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2017; Nature Publishing Group
• Subjects: 13/2; 13/31; 14/34; 14/63; 631/67/1059; 631/67/1990/283/1897; 631/67/68; 64/60; 692/4028/67/2327; 82/29; Acute myelocytic leukemia; Acute myeloid leukemia; Adaptation; Adaptations; Adenosine Triphosphate - metabolism; AKT protein; Animal models; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer Research; Care and treatment; Cell death; Cell Line; Cell Transformation, Neoplastic; Critical Care Medicine; Cytotoxicity; Deoxyglucose - pharmacology; Depletion; Development and progression; Enzyme inhibitors; Flt3 protein; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - physiology; Gene mutation; Genetic aspects; Glycolysis; Glycolysis - drug effects; Glycolysis - genetics; Health aspects; Hematology; Hematopoietic Stem Cells - cytology; Hexokinase; Hexokinase - biosynthesis; Hexokinase - genetics; Humans; Hydrocarbons, Brominated - pharmacology; Inhibition; Intensive; Internal Medicine; Intervention; Kinases; Leukemia; Leukemia, Experimental - drug therapy; Medicine; Medicine & Public Health; Metabolism; Mice; Mice, Inbred BALB C; Microsatellite Repeats; Mitochondria; Mitochondria - enzymology; Molecular Targeted Therapy; Mutation; Myeloid leukemia; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Niacinamide - therapeutic use; Oncogenes; Oncology; Original; original-article; Pharmacology; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Propionates - pharmacology; Protein-tyrosine kinase; Proto-Oncogene Proteins c-akt - metabolism; Toxicity; Tumors; Tyrosine
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.45

Internal tandem duplication (ITD) mutation in Fms-like tyrosine kinase 3 gene (FLT3/ITD) represents an unfavorable genetic change in acute myeloid leukemia (AML) and is associated with poor prognosis. Metabolic alterations have been involved in tumor progression and attracted interest as a target for therapeutic intervention. However, few studies analyzed the adaptations of cellular metabolism in the context of FLT3/ITD mutation. Here, we report that FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity. Inhibition of glycolysis preferentially causes severe ATP depletion and massive cell death in FLT3/ITD leukemia cells. Glycolytic inhibitors significantly enhances the cytotoxicity induced by FLT3 tyrosine kinase inhibitor sorafenib. Importantly, such combination provides substantial therapeutic benefit in a murine model bearing FLT3/ITD leukemia. Our study suggests that FLT3/ITD mutation promotes Warburg effect, and such metabolic alteration can be exploited to develop effective therapeutic strategy for treatment of AML with FLT3/ITD mutation via metabolic intervention.