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Reiter, K.* ; Polzer, H.* ; Krupka, C.* ; Maiser, A.* ; Vick, B. ; Rothenberg-Thurley, M.* ; Metzeler, K.H.* ; Dörfel, D.* ; Salih, H.R.* ; Jung, G.* ; Nößner, E. ; Jeremias, I.* ; Hiddemann, W.* ; Leonhardt, H.* ; Spiekermann, K.* ; Subklewe, M.* ; Greif, P.A.*

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

Leukemia 32, 313-322 (2018)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Flt3-kinase Inhibitors; Wild-type; Amg 330; Mutations; Resistance; Sorafenib; Receptor; Antibody; Activation; Lymphoma
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 32, Issue: 2, Pages: 313-322 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Institute of Virology (VIRO)