title: Interferon-alpha, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia.
abstract: Chronic myeloid leukemia (CML) is a clonal disease of hematopoietic stem cells caused by a reciprocal translocation of the long arms of chromosomes 9 and 22. In human leukocyte antigen A*0201(+) (HLA-A*0201(+)) individuals, response after interferon-alpha (IFN-alpha) was shown to be associated with the emergence of CML-specific cytotoxic T cells that recognize PR-1, a myeloblastin (MBN)-derived nonapeptide. In contrast, imatinib potently induces remissions from CML by specific inhibition of the ABL tyrosine kinase. Here, we explored molecular regulations associated with CML responses under different treatment forms using cDNA-array. Expression of MBN was found to be down-regulated in remission under imatinib therapy (0 of 7 MBN(+) patients). In contrast, MBN transcription was readily detectable in the peripheral blood in 8 of 8 tested IFN-alpha patients in complete remission (P =.0002). IFN-alpha-dependent MBN transcription was confirmed in vitro by stimulation of peripheral blood mononuclear cells (PBMCs) with IFN-alpha and by IFN-alpha-mediated activation of the MBN promoter in reporter gene assays. Finally, with the use of HLA-A*0201-restricted, MBN-specific tetrameric complexes, it was demonstrated that all of 4 IFN-alpha-treated patients (100%), but only 2 of 11 imatinib patients (19%), in complete hematological or cytogenetic remission developed MBN-specific cytotoxic T cells (P =.011). Together, the induction of MBN expression by IFN-alpha, but not imatinib, may contribute to the specific ability of IFN-alpha to induce an MBN-specific T-cell response in CML patients. This also implies that the character of remissions achieved with either drug may not be equivalent and therefore a therapy modality combining IFN-alpha and imatinib may be most effective.
authors.affiliation: Klinikum der Philipps Universität Marburg, Klinik für Hämatologie, Onkologie und Immunologie, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Burchert
authors.forename: Stefan
authors.initials: S
authors.lastname: Wölfl
authors.forename: Manuel
authors.initials: M
authors.lastname: Schmidt
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brendel
authors.forename: Barbara
authors.initials: B
authors.lastname: Denecke
authors.forename: Dali
authors.initials: D
authors.lastname: Cai
authors.forename: Larissa
authors.initials: L
authors.lastname: Odyvanova
authors.forename: Tanja
authors.initials: T
authors.lastname: Lahaye
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Harald
authors.initials: H
authors.lastname: Gschaidmeier
authors.forename: Burghardt
authors.initials: B
authors.lastname: Wittig
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Hehlmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Andreas
authors.initials: A
authors.lastname: Neubauer
mesh_terms: D001549:Benzamides; D016022:Case-Control Studies; D016172:DNA Fingerprinting; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D009000:Monocytes / Q000187:drug effects; D053146:Myeloblastin; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012074:Remission Induction / Q000379:methods; D012697:Serine Endopeptidases / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001549:Benzamides; D016898:Interferon-alpha; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D012697:Serine Endopeptidases; D053146:Myeloblastin