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Blood, 1 May 2004, Vol. 103, No. 9, pp. 3480-3489.
Prepublished online as a Blood First Edition Paper on December 4, 2003; DOI 10.1182/blood-2003-08-2970.
Submitted September 2, 2003
Accepted November 21, 2003
Interferon Consensus Sequence Binding Protein (ICSBP, IRF-8) antagonizes BCR/ABL and down-regulates bcl-2
Andreas Burchert, Dali Cai, Lorenz Hofbauer, Magnus K R Samuelsson, Emily P Slater, Justus Duyster, Markus Ritter, Andreas Hochhaus, Rolf Mueller, Martin Eilers, Manuel Schmidt, and Andreas Neubauer*
Department of Hematology/Oncology and Immunology, Philipps University, Marburg, Germany
Department of Gastroenterology and Endocrinology, Philipps University, Marburg, Germany
Department of Medicine, Institute of Molecular Biology and Tumor Research, Philipps University, Marburg, Germany
Department of Internal Medicine III, Laboratory of Leukemogenesis, Technical University of Munich, Munich, Germany
Department of Clinical Medicine Mannheim, III. Medical Clinic, University Heidelberg, Mannheim, Germany
Mologen GmbH, Berlin, Germany
* Corresponding author; email: neubauer{at}mailer.uni-marburg.de.
BCR/ABL is the causative genetic aberration in chronic myelogenous leukemia (CML). Mice lacking expression of the interferon (IFN) consensus binding protein (ICSBP), an IFN - inducible transcription factor of the interferon regulatory factor (IRF)-family, develop a disease similar to human CML. Mounting evidence suggests a role for ICSBP in the pathogenesis of CML. However, the underlying mechanisms are largely unknown. By stable and conditional expression of ICSBP in wild-type, and BCR/ABL-transformed 32D cells (32D-wt and 32D-BA), we found that ICSBP inhibited BCR/ABL-mediated leukemogenesis in vivo. Moreover, ICSBP also overrode BCR/ABL-mediated morphology changes, chemo-, and imatinib resistance, as well as BCR/ABL-induced repression of differentiation. Some of these ICSBP-effects may be explained in part by an ICSBP-mediated repression of bcl-2, a major anti-apoptotic target of BCR/ABL, on transcriptional and protein level. Using reporter gene assays and electrophoretic mobility shift assays we identified that the bcl-2 promoter activity was inhibited by ICSBP via a fragment containing two characteristic ICSBP-responsive elements. An inverse correlation between ICSBP and bcl-2 expression was confirmed in vivo. Collectively, our findings suggest that ICSBP antagonizes BCR/ABL by down-regulation of bcl-2 and implicates a central role for ICSBP in the pathogenesis of CML, as well as a therapeutic target to overcome drug resistance in bcl-2 dependent tumors.
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