机构：[1]Sun Yat-sen University Cancer Center中山大学肿瘤防治中心[2]Department of Hematology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China内科科室血液内科中山大学附属第一医院[3]Department of Hematology, The Second Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China[4]Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[5]Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.[6]State Key Laboratory of Oncology in South China其他部门华南肿瘤学国家重点实验室中山大学肿瘤防治中心[7]Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
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.
基金：
Guangdong Natural Science Foundation [2014A030313037]; National Basic Research Program of China (973 program) [2013CB910304]; Guangzhou Innovation Research Program [LCY201317]; Guangzhou Technology Program [201508020250]
语种：
外文
被引次数：
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|1 区医学
小类|1 区血液学1 区肿瘤学
最新[2023]版：
大类|1 区医学
小类|1 区血液学1 区肿瘤学
第一作者：
第一作者机构：[1]Sun Yat-sen University Cancer Center[6]State Key Laboratory of Oncology in South China[7]Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
共同第一作者：
通讯作者：
通讯机构：[1]Sun Yat-sen University Cancer Center[4]Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[5]Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.[6]State Key Laboratory of Oncology in South China[7]Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China[*]Experimental Research, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, China.
推荐引用方式(GB/T 7714)：
H-Q Ju,G Zhan,A Huang,et al.ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition[J].LEUKEMIA.2017,31(10):2143-2150.doi:10.1038/leu.2017.45.
APA：
H-Q Ju,G Zhan,A Huang,Y Sun,S Wen...&Y Hu.(2017).ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition.LEUKEMIA,31,(10)
MLA：
H-Q Ju,et al."ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition".LEUKEMIA 31..10(2017):2143-2150
医学