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Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells
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 nearl...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930553/ https://www.ncbi.nlm.nih.gov/pubmed/29716633 http://dx.doi.org/10.1186/s13045-018-0603-7 |
Sumario: | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13045-018-0603-7) contains supplementary material, which is available to authorized users. |
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