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Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells
by
Xu, Yingxi
, Xing, Haiyan
, Tian, Zheng
, Xing, Yanyan
, Li, Saisai
, Wang, Ying
, Wang, Jianxiang
, Rao, Qing
, Wang, Min
, Liu, Jia
, Tang, Kejing
in
Acute myeloid leukemia
/ Cancer Research
/ Chimeric antigen receptor
/ FLT3
/ FLT3-ITD
/ Genetic aspects
/ Hematology
/ Immunotherapy
/ Medicine
/ Medicine & Public Health
/ Oncology
/ Physiological aspects
/ Protein tyrosine kinase
/ T cells
2018
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Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells
by
Xu, Yingxi
, Xing, Haiyan
, Tian, Zheng
, Xing, Yanyan
, Li, Saisai
, Wang, Ying
, Wang, Jianxiang
, Rao, Qing
, Wang, Min
, Liu, Jia
, Tang, Kejing
in
Acute myeloid leukemia
/ Cancer Research
/ Chimeric antigen receptor
/ FLT3
/ FLT3-ITD
/ Genetic aspects
/ Hematology
/ Immunotherapy
/ Medicine
/ Medicine & Public Health
/ Oncology
/ Physiological aspects
/ Protein tyrosine kinase
/ T cells
2018
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Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells
by
Xu, Yingxi
, Xing, Haiyan
, Tian, Zheng
, Xing, Yanyan
, Li, Saisai
, Wang, Ying
, Wang, Jianxiang
, Rao, Qing
, Wang, Min
, Liu, Jia
, Tang, Kejing
in
Acute myeloid leukemia
/ Cancer Research
/ Chimeric antigen receptor
/ FLT3
/ FLT3-ITD
/ Genetic aspects
/ Hematology
/ Immunotherapy
/ Medicine
/ Medicine & Public Health
/ Oncology
/ Physiological aspects
/ Protein tyrosine kinase
/ T cells
2018
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Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells
Journal Article
Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells
2018
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Overview
Background
Chimeric antigen receptor-engineered T (CAR-T) cells have extraordinary effect in treating lymphoblastic leukemia. However, treatment of acute myeloid leukemia (AML) using CAR-T cells remains limited to date. Leukemogenesis always relates with the abnormalities of cytogenetics, and nearly one third of AML patients have activating mutations in Fms-like tyrosine kinase 3 (FLT3) which reminded poor prognosis. Considering the FLT3 expressed in AML patients’ blast cells, it may be a new candidate target for CAR-T therapy to treat FLT3
+
AML, especially patients harboring FLT3-ITD mutation.
Methods
The FLT3L CAR-T using FLT3 ligand as recognizing domain was constructed. The specific cytotoxicity against FLT3
+
leukemia cell lines, primary AML cells, and normal hematopoietic progenitor stem cells (HPSCs) in vitro were evaluated. In addition, FLT3
+
AML mouse model was used to assess the effect of FLT3L CAR-T therapy in vivo.
Results
FLT3L CAR-T cells could specifically kill FLT3
+
leukemia cell lines and AML patients’ bone marrow mononuclear cells in vitro (with or without FLT3 mutation) and have more potent cytotoxicity to FLT3-ITD cells. In a human FLT3
+
AML xenograft mouse model, FLT3L CAR-T cells could significantly prolong the survival of mice. Furthermore, it was found that FLT3L CAR-T cells could activate the FLT3/ERK signaling pathway of FLT3
+
leukemia cells with wild-type FLT3; meanwhile, it had no inhibitory effects on the colony formation of CD34
+
stem cells derived from normal human umbilical cord blood.
Conclusions
The ligand-based FLT3L CAR-T cells could be a promising strategy for FLT3
+
AML treatment, especially those carried FLT3 mutation.
Publisher
BioMed Central,BioMed Central Ltd,BMC
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