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Induction of interferon regulatory factors, 2′‐5′ oligoadenylate synthetase, P68 kinase and RNase L in chronic myelogenous leukaemia cells and its relationship to clinical responsiveness
Author(s) -
Fischer Thomas,
Aman Javad,
Van DerKuip Heiko,
Rudolf Gregor,
Peschel Christian,
Aulitzky Walter,
Huber Christoph
Publication year - 1996
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.1996.00392.x
Subject(s) - interferon regulatory factors , biology , interferon , chronic myelogenous leukemia , immunology , irf1 , peripheral blood mononuclear cell , northern blot , alpha interferon , cancer research , microbiology and biotechnology , gene expression , immune system , gene , leukemia , in vitro , genetics , innate immune system
The genes crucially determining the therapeutic response of chronic myelogenous leukaemia (CML) to interferon‐alpha (IFN‐alpha) are unknown. Recently, two independent IFN‐alpha signalling pathways were identified: the classic pathway mediates induction of 2′‐5′ oligoadenylate synthetase (2‐5 OAS), p68 kinase and IFN regulatory factor‐2 (IRF‐2), whereas the alternate pathway leads to activation of IFN regulatory factor‐1 (IRF‐1). We investigated whether deficient or imbalanced expression of components of these two pathways is associated with resistance of CML cells to antiproliferative action of IFN‐alpha/beta. Constitutive and IFN‐induced transcript levels of IFN‐dependent genes in mononuclear cells, granulocytes, monocytes, lymphocytes and CD34 + cells of chronic‐phase CML and blast crisis patients were assessed by Northern blot techniques and were correlated with subsequent clinical responses to IFN therapy. Our results demonstrated that IFN‐alpha or ‐beta treatment in vitro and in vivo leads to an enhanced expression of IRF‐1, IRF‐2, RNase L, p68 and 2‐5 OAS which was independent of the degree of cellular differentiation and clonal evolution of CML. Neither the magnitude of induction of these genes nor the IRF‐1/IRF‐2 mRNA balance differed between chronic‐phase CML patients responding or failing IFN‐alpha therapy. These results indicate that failure of IFN‐alpha treatment is not due to defects in mRNA induction of the above‐mentioned candidate genes for the direct antiproliferative response to IFN type I.