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SHP-1 inhibition targets leukaemia stem cells to restore immunosurveillance and enhance chemosensitivity by metabolic reprogramming.
Xu, Xi; Yu, Yanhui; Zhang, Wenwen; Ma, Weiwei; He, Chong; Qiu, Guo; Wang, Xinyi; Liu, Qiong; Zhao, Minyi; Xie, Jiayi; Tao, Fang; Perry, John M; Liu, Qifa; Rao, Shuan; Kang, Xunlei; Zhao, Meng; Jiang, Linjia.
Afiliación
  • Xu X; RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • Yu Y; Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Zhang W; Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University Guangzhou, Guangdong, China.
  • Ma W; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • He C; Department of Hematology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, China.
  • Qiu G; Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University Guangzhou, Guangdong, China.
  • Wang X; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • Liu Q; Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University Guangzhou, Guangdong, China.
  • Zhao M; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • Xie J; RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • Tao F; Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University Guangzhou, Guangdong, China.
  • Perry JM; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • Liu Q; Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Rao S; RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • Kang X; Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University Guangzhou, Guangdong, China.
  • Zhao M; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • Jiang L; Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Nat Cell Biol ; 26(3): 464-477, 2024 Mar.
Article en En | MEDLINE | ID: mdl-38321204
ABSTRACT
Leukaemia stem cells (LSCs) in acute myeloid leukaemia present a considerable treatment challenge due to their resistance to chemotherapy and immunosurveillance. The connection between these properties in LSCs remains poorly understood. Here we demonstrate that inhibition of tyrosine phosphatase SHP-1 in LSCs increases their glycolysis and oxidative phosphorylation, enhancing their sensitivity to chemotherapy and vulnerability to immunosurveillance. Mechanistically, SHP-1 inhibition leads to the upregulation of phosphofructokinase platelet (PFKP) through the AKT-ß-catenin pathway. The increase in PFKP elevates energy metabolic activities and, as a consequence, enhances the sensitivity of LSCs to chemotherapeutic agents. Moreover, the upregulation of PFKP promotes MYC degradation and, consequently, reduces the immune evasion abilities of LSCs. Overall, our study demonstrates that targeting SHP-1 disrupts the metabolic balance in LSCs, thereby increasing their vulnerability to chemotherapy and immunosurveillance. This approach offers a promising strategy to overcome LSC resistance in acute myeloid leukaemia.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Reprogramación Metabólica Límite: Humans Idioma: En Revista: Nat Cell Biol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Reprogramación Metabólica Límite: Humans Idioma: En Revista: Nat Cell Biol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido