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A combinatorial therapeutic approach to enhance FLT3-ITD AML treatment.
Long, Jun; Chen, Xinjie; Shen, Yan; Lei, Yichen; Mu, Lili; Wang, Zhen; Xiang, Rufang; Gao, Wenhui; Wang, Lining; Wang, Ling; Jiang, Jieling; Zhang, Wenjun; Lu, Huina; Dong, Yan; Ding, Yi; Zhu, Honghu; Hong, Dengli; Sun, Yi Eve; Hu, Jiong; Liang, Aibin.
Affiliation
  • Long J; Department of Hematology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China; Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Ton
  • Chen X; Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Shen Y; State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Lei Y; Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Mu L; Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Wang Z; Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
  • Xiang R; Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Gao W; Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Wang L; Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Wang L; Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Jiang J; Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zhang W; Department of Hematology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
  • Lu H; Department of Hematology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
  • Dong Y; Department of Hematology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
  • Ding Y; Department of Hematology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
  • Zhu H; Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
  • Hong D; Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: dl
  • Sun YE; Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: yi.eve.sun@gmail.com.
  • Hu J; Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: hj10709@rjh.com.cn.
  • Liang A; Department of Hematology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: lab7182@tongji.edu.cn.
Cell Rep Med ; 4(11): 101286, 2023 11 21.
Article in En | MEDLINE | ID: mdl-37951217
ABSTRACT
Internal tandem duplication mutations of the FMS-like tyrosine kinase-3 (FLT3-ITDs) occur in 25%-30% of patients with acute myeloid leukemia (AML) and are associated with dismal prognosis. Although FLT3 inhibitors have demonstrated initial clinical efficacy, the overall outcome of patients with FLT3-ITD AML remains poor, highlighting the urgency to develop more effective treatment strategies. In this study, we reveal that FLT3 inhibitors reduced protein stability of the anti-cancer protein p53, resulting in drug resistance. Blocking p53 degradation with proteasome inhibitors restores intracellular p53 protein levels and, in combination with FLT3-ITD inhibitors, shows superior therapeutic effects against FLT3-ITD AML in cells, mouse models, and patients. These data suggest that this combinatorial therapeutic approach may represent a promising strategy to target FLT3-ITD AML.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Leukemia, Myeloid, Acute / Tumor Suppressor Protein p53 Limits: Animals / Humans Language: En Journal: Cell Rep Med Year: 2023 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Leukemia, Myeloid, Acute / Tumor Suppressor Protein p53 Limits: Animals / Humans Language: En Journal: Cell Rep Med Year: 2023 Document type: Article