BCR-ABL activity is critical for the immunogenicity of chronic myelogenous leukemia cells.
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder caused by excessive granulopoiesis due to the formation of the constitutively active tyrosine kinase BCR-ABL. An effective drug against CML is imatinib mesylate, a tyrosine kinase inhibitor acting on Abl kinases, c-KIT, and platelet-derived growth factor receptor. Recently, a study revealed that patients treated with imatinib showed impaired CTL responses compared with patients treated with IFN-alpha, which might be due to a treatment-induced reduction in immunogenicity of CML cells or immunosuppressive effects. In our study, we found that inhibition of BCR-ABL leads to a down-regulation of immunogenic antigens on the CML cells in response to imatinib treatment, which results in the inhibition of CML-directed immune responses. By treating CML cells with imatinib, we could show that the resulting inhibition of BCR-ABL leads to a decreased expression of tumor antigens, including survivin, adipophilin, hTERT, WT-1, Bcl-x(L), and Bcl-2 in correlation to a decreased development of CML-specific CTLs. In contrast, this reduction in immunogenicity was not observed when a CML cell line resistant to the inhibitory effects of imatinib was used, but could be confirmed by transfection with specific small interfering RNA against BCR-ABL or imatinib treatment of primary CML cells.
Brauer
Katharina M
KM
Department of Hematology, Oncology, Immunology, Rheumatology, and Pulmonology, University of Tübingen, Tübingen, Germany.
Werth
Daniela
D
von Schwarzenberg
Karin
K
Bringmann
Anita
A
Kanz
Lothar
L
Grünebach
Frank
F
Brossart
Peter
P
D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D003713:Dendritic Cells / Q000276:immunology; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000276:immunology*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl