title: Flt3-ITD mutations can generate leukaemia specific neoepitopes: potential role for immunotherapeutic approaches.
abstract: Flt3 internal tandem duplications (Flt3-ITD) can be detected in 25 - 30% of acute myeloid leukaemia (AML) and differ in length and sequence. We sequenced patient specific Flt3-ITD mutations in 2 Flt3-ITD positive AML cell lines and 13 Flt3-ITD harbouring AML patients. We addressed the question whether Flt3-ITD mutations can harbour HLA class I specific neoepitopes potentially able to induce a leukaemia and Flt3-ITD specific immune response. Here, we demonstrate that all but 1 Flt3-ITD mutations were unique. Interestingly, the peptide sequence of several Flt3-ITD fusion regions harbour 9 mer neoepitopes that potentially bind to HLA class I molecules in a HLA restricted manner (e.g. A1, A2, B27). The specific binding of Flt3-ITD derived neoepitopes to HLA-A2 is demonstrated. Peptide affinity of HLA-A2-restricted putative neoepitopes can be significantly improved by construction of mimotope candidates. We suggest that Flt3-ITD mutations can form new immunogenic and HLA class I-restricted peptide epitopes.
authors.affiliation: Department of Internal Medicine II, Oncology and Hematology, Friedrich Schiller University, Jena, Germany. sebastian.scholl@med.uni-jena.de
authors.forename: S
authors.initials: S
authors.lastname: Scholl
authors.forename: S
authors.initials: S
authors.lastname: Salzmann
authors.forename: A M
authors.initials: AM
authors.lastname: Kaufmann
authors.forename: K
authors.initials: K
authors.lastname: Höffken
mesh_terms: D000208:Acute Disease; D045744:Cell Line, Tumor; D000939:Epitopes / Q000235:genetics* / Q000276:immunology; D005805:Genes, MHC Class I / Q000235:genetics / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D009154:Mutation; D010446:Peptide Fragments / Q000276:immunology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000276:immunology
chemical_list: D000939:Epitopes; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3