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Interferon consensus sequence binding protein (ICSBP; IRF-8) antagonizes BCR/ABL and down-regulates bcl-2
Andreas Burchert1, Dali Cai, Lorenz C Hofbauer
1Klinikum der Philipps Universität Marburg, Klinik für Hämatologie, Onkologie und Immunologie, Marburg, Germany.
Blood
|December 6, 2003
Summary
Interferon consensus sequence binding protein (ICSBP) inhibits BCR/ABL-driven leukemia in mice. ICSBP antagonizes BCR/ABL by down-regulating bcl-2, offering a potential therapeutic strategy for CML and drug resistance.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- BCR/ABL is the primary cause of chronic myelogenous leukemia (CML).
- Mice lacking interferon consensus sequence binding protein (ICSBP) develop CML-like disease.
- The precise role of ICSBP in CML pathogenesis remains unclear.
Purpose of the Study:
- To investigate the role of ICSBP in BCR/ABL-mediated leukemogenesis.
- To elucidate the mechanisms by which ICSBP affects CML.
- To explore ICSBP as a potential therapeutic target.
Main Methods:
- Stable and conditional expression of ICSBP in 32D cell lines (wild-type and BCR/ABL-transformed).
- In vivo leukemogenesis assays.
- Reporter gene assays and electrophoretic mobility shift assays to study gene regulation.
- Analysis of bcl-2 expression at transcriptional and protein levels.
Main Results:
- ICSBP significantly inhibited BCR/ABL-mediated leukemogenesis in vivo.
- ICSBP reversed BCR/ABL-induced resistance to chemotherapy and imatinib.
- ICSBP repressed bcl-2 expression transcriptionally and at the protein level.
- ICSBP directly inhibited the bcl-2 promoter via specific responsive elements.
Conclusions:
- ICSBP antagonizes BCR/ABL by down-regulating the antiapoptotic gene bcl-2.
- ICSBP plays a crucial role in CML pathogenesis.
- Targeting ICSBP may overcome drug resistance in bcl-2-dependent tumors.