Interferon-alpha, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia.

Publikation

Interferon-alpha, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia.

Wissenschaftlicher Artikel/Review - 28.06.2002

Burchert Andreas, Wölfl Stefan, Schmidt Manuel, Brendel Cornelia, Denecke Barbara, Cai Dali, Odyvanova Larissa, Lahaye Tanja, Müller Martin, Berg Thomas, Gschaidmeier Harald, Wittig Burghardt, Hehlmann Rüdiger, Hochhaus Andreas, Neubauer Andreas

Zitation

Burchert A, Wölfl S, Schmidt M, Brendel C, Denecke B, Cai D, Odyvanova L, Lahaye T, Müller M, Berg T, Gschaidmeier H, Wittig B, Hehlmann R, Hochhaus A, Neubauer A. Interferon-alpha, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia. Blood 2002; 101:259-64.

Art

Wissenschaftlicher Artikel/Review (Englisch)

Zeitschrift

Blood 2002; 101

Veröffentlichungsdatum

28.06.2002

ISSN (Druck)

0006-4971

Seiten

259-64

Kurzbeschreibung/Zielsetzung

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.