The immunogenicity of Bcr-Abl expressing dendritic cells is dependent on the Bcr-Abl kinase activity and dominated by Bcr-Abl regulated antigens.
In Ph(+) chronic myeloid leukemia (CML), the constitutively active Bcr-Abl kinase leads to the up-regulation and activation of multiple genes, which may subsequently result in the expression of leukemia-associated antigens. In this study, we investigated the immunogenicity of Bcr-Abl-regulated antigens by stimulating CD8(+) T lymphocytes with autologous dendritic cells transfected with RNA coding for Bcr-Abl wild-type or a kinase-deficient mutant. Significant HLA class I-restricted T-cell responses were detected against antigens regulated by the Bcr-Abl kinase, but not toward the Bcr-Abl protein itself. The T-cell repertoire of a patient with CML in major molecular remission due to imatinib mesylate was also dominated by T cells directed against Bcr-Abl-regulated antigens. These results encourage the development of immunotherapeutic approaches against Bcr-Abl-regulated antigens for the treatment of CML patients with residual disease following therapy with Bcr-Abl kinase inhibitors.
Scheich
Florian
F
Department of Hematology/Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Duyster
Justus
J
Peschel
Christian
C
Bernhard
Helga
H
D000818:Animals; D000941:Antigens / Q000276:immunology*; D001549:Benzamides; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007125:Immunogenetics; D007938:Leukemia / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015854:Up-Regulation; D014982:Xenopus laevis
D000941:Antigens; D001549:Benzamides; D006680:HLA Antigens; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl