Format

Send to

Choose Destination
Leukemia. 2018 Feb;32(2):313-322. doi: 10.1038/leu.2017.257. Epub 2017 Aug 14.

Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia.

Author information

1
Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.
2
German Cancer Consortium (DKTK), partner site Munich, Munich, Germany.
3
German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Department of Translational Cancer Immunology, Gene Center Munich, LMU Munich, Munich, Germany.
5
Department of BioIogy II, LMU Munich, Munich, Germany.
6
Department of Gene Vectors, Helmholtz Zentrum München, German Research center for Enviromental Health, Munich, Germany.
7
Department of Medical Oncology, Hematology, Immunology, Rheumatology and Pulmology, Eberhard Karls Universität Tübingen, University Hospital Tübingen, Tübingen, Germany.
8
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Tübingen, Tübingen, Germany.
9
Department of Immunology, Eberhard Karls Universität Tübingen, Tübingen, Germany.
10
Immunoanalytics-Tissue control of Immunocytes, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
11
Department of Pediatrics, Dr von Hauner Children's Hospital, LMU Munich, Munich, Germany.

Abstract

The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regard to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) became of special interest in this setting as they are associated with unfavorable prognosis. Because of sequence-dependent protein conformational changes FLT3-ITD tends to autophosphorylate and displays a constitutive intracellular localization. Here, we analyzed the effect of tyrosine kinase inhibitors (TKIs) on the localization of the FLT3 receptor and its mutants. TKI treatment increased the surface expression through upregulation of FLT3 and glycosylation of FLT3-ITD and FLT3-D835Y mutants. In T cell-mediated cytotoxicity (TCMC) assays, using a bispecific FLT3 × CD3 antibody construct, the combination with TKI treatment increased TCMC in the FLT3-ITD-positive AML cell lines MOLM-13 and MV4-11, patient-derived xenograft cells and primary patient samples. Our findings provide the basis for rational combination of TKI and FLT3-directed immunotherapy with potential benefit for FLT3-ITD-positive AML patients.

PMID:
28895560
PMCID:
PMC5808080
DOI:
10.1038/leu.2017.257
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center