A neoepitope generated by an FLT3 internal tandem duplication (FLT3-ITD) is recognized by leukemia-reactive autologous CD8+ T cells.
The FLT3 receptor tyrosine kinase is expressed in more than 90% of acute myelogeneous leukemias (AMLs), up to 30% of which carry an internal tandem duplication (ITD) within the FLT3 gene. Although varying duplication sites exist, most FLT3-ITDs affect a single protein domain. We analyzed the FLT3-ITD of an AML patient for encoding HLA class I-restricted immunogenic peptides. One of the tested peptides (YVDFREYEYY) induced in vitro autologous T-cell responses restricted by HLA-A*0101 that were also detectable ex vivo. These peptide-reactive T cells recognized targets transfected with the patient's FLT3-ITD, but not wild-type FLT3, and recognized the patient's AML cells. Our results demonstrate that AML leukemic blasts can in principle process and present immunogenic FLT3-ITD neoepitopes. Therefore, FLT3-ITD represents a potential candidate target antigen for the immunotherapy of AML.
Graf
Claudine
C
III Medizinische Klinik, Johannes Gutenberg-Universität, Mainz, Germany.
Heidel
Florian
F
Tenzer
Stefan
S
Radsak
Markus P
MP
Solem
Fian K
FK
Britten
Cedrik M
CM
Huber
Christoph
C
Fischer
Thomas
T
Wölfel
Thomas
T
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D000939:Epitopes / Q000235:genetics; D020440:Gene Duplication; D015234:HLA-A Antigens / Q000235:genetics / Q000378:metabolism; D015788:HLA-A1 Antigen; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D014162:Transfection; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000276:immunology*
D000939:Epitopes; D015234:HLA-A Antigens; C506470:HLA-A*01:01 antigen; D015788:HLA-A1 Antigen; D012333:RNA, Messenger; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3