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.

Keywords:

• AML
• Flt3-ITD
• neoepitope
• mimotope
• immunotherapy