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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
PubMed

Insights

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.

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