title: ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition.
abstract: 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.
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: H-Q
authors.initials: HQ
authors.lastname: Ju
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: G
authors.initials: G
authors.lastname: Zhan
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: A
authors.initials: A
authors.lastname: Huang
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: S
authors.initials: S
authors.lastname: Wen
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: W-H
authors.initials: WH
authors.lastname: Lu
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: R-H
authors.initials: RH
authors.lastname: Xu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hematology, The Second Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.|Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Huang
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D003847:Deoxyglucose / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006593:Hexokinase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000494:pharmacology; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018895:Microsatellite Repeats; D008928:Mitochondria / Q000201:enzymology; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011422:Propionates / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077157:Sorafenib; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology
chemical_list: C568307:3-bromo-2-oxopropionate-1-propyl ester; D000970:Antineoplastic Agents; D006842:Hydrocarbons, Brominated; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D011422:Propionates; D009536:Niacinamide; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D000077157:Sorafenib; D006593:Hexokinase; C000598049:hexokinase 2, mouse; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D051057:Proto-Oncogene Proteins c-akt