Spatial metabolomics highlights metabolic reprogramming in acute myeloid leukemia mice through creatine pathway  

作　　者：Yucheng Bao Jing Qiao Wenjie Gong Ruihong Zhang Yanting Zhou Yinyin Xie Yuan Xie Jiuming He Tong Yin 

机构地区：[1]Shanghai Institute of Hematology,State Key Laboratory of Medical Genomics,National Research Centre for Translational Medicine at Shanghai,Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [2]College of Osteopathic Medicine,Kansas City University,Kansas City,MO 64106,USA [3]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China [4]NMPA Key Laboratory for Safety Research and Evaluation of Innovative Drug,Beijing 100050,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第10期4461-4477,共17页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.81770124);the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(RC20210190,China)。

摘　　要：Acute myeloid leukemia(AML)is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming.Here,we applied spatial metabolomics to achieve high-throughput,in situ identification of metabolites within the liver metastases of AML mice.Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics.This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle,coupled with an upregulation of the creatine metabolism.The upregulation of creatine synthetases Gatm and Gamt,as well as the creatine transporter Slc6a8,resulted in a marked accumulation of creatine within tumor foci.This process further enhances oxidative phosphorylation and glycolysis of leukemia cells,thereby boosting ATP production to foster proliferation and infiltration.Importantly,we discovered that inhibiting Slc6a8 can counter these detrimental effects,offering a new strategy for treating AML by targeting metabolic pathways.

关 键 词：Spatial metabolomics Acute myeloid leukemia Metabolic reprogramming CREATINE Slc6a8 Oxidative phosphorylation GLYCOLYSIS Metastasis 

分 类 号：R587.2[医药卫生—内分泌] R692.9[医药卫生—内科学]