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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)
Verlagsversion DOI PMC
Free by publisher
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Flt3-kinase Inhibitors; Wild-type; Amg 330; Mutations; Resistance; Sorafenib; Receptor; Antibody; Activation; Lymphoma
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Zeitschrift Leukemia
Quellenangaben Band: 32, Heft: 2, Seiten: 313-322 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Institute of Virology (VIRO)