Abstract

The FMS-like tyrosine kinase 3 (FLT3) is highly expressed in acute myeloid leukemia (AML). Internal tandem duplications (ITD) of the juxtamembrane domain lead to the constitutive activation of the FLT3 kinase inducing the activation of multiple genes, which may result in the expression of leukemia-associated antigens (LAAs). We analyzed the regulation of LAA in FLT3-wild-type (WT)- and FLT3-ITD+ myeloid cells to identify potential targets for antigen-specific immunotherapy for AML patients. Antigens, such as PR-3, RHAMM, Survivin, WT-1 and PRAME, were upregulated by constitutively active FLT3-ITD as well as FLT3-WT activated by FLT3 ligand (FL). Cytotoxic T-cell (CTL) clones against PR-3, RHAMM, Survivin and an AML-directed CTL clone recognized AML cell lines and primary AML blasts expressing FLT3-ITD, as well as FLT3-WT+ myeloid dendritic cells in the presence of FL. Downregulation of FLT3 led to the abolishment of CTL recognition. Comparing our findings concerning LAA upregulation by the FLT3 kinase with those already made for the Bcr-Abl kinase, we found analogies in the LAA expression pattern. Antigens upregulated by both FLT3 and Bcr-Abl may be promising targets for the development of immunotherapeutical approaches against myeloid leukemia of different origin.

Highlights

  • The FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is highly expressed by malignant cells in most cases of acute myeloid leukemia (AML) and acute B-lineage leukemia (ALL).[1,2] In addition, FLT3 mutations belong to the most frequent somatic alterations in AML and occur in approximately 30% of AML patients.[3]

  • We show that a panel of leukemia-associated antigens (LAA), such as PR-3, Survivin and RHAMM, is upregulated by constitutively active FLT3-internal tandem duplications (ITDs)

  • The Rhamm-specific CTL clone JG9E5 showed about 100% lysis dependency of this expression on the FLT3 kinase activity could of RHAMM165À173-loaded T2 cells at higher E:T ratios and up to 40% lysis of K562tA2 cells (Figure 2c, middle)

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Summary

Introduction

The FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is highly expressed by malignant cells in most cases of acute myeloid leukemia (AML) and acute B-lineage leukemia (ALL).[1,2] In addition, FLT3 mutations belong to the most frequent somatic alterations in AML and occur in approximately 30% of AML patients.[3]. It has been shown in clinical studies that AML patients harboring FLT3-ITD mutations have a poor prognosis.[6,7]

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