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Prepublished online as a Blood First Edition Paper on August 21, 2003; DOI 10.1182/blood-2003-01-0291.
Submitted January 31, 2003
Accepted August 14, 2003
ICSBP/IRF-8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating myeloid progenitor cells
Tomohiko Tamura, Hee Jeong Kong, Chainarong Tunyaplin, Hideki Tsujimura, Kathryn Calame, and Keiko Ozato*
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, NY, USA
* Corresponding author; email: ozatok{at}mail.nih.gov.
Interferon consensus sequence binding protein (ICSBP/IRF-8) is a transcription factor that controls myeloid cell development. ICSBP-/- mice develop a chronic myelogenous leukemia (CML)-like syndrome. Several observations on patients and mouse models have implicated the role for ICSBP in the pathogenesis of CML. In this paper, we investigated whether ICSBP modulates the growth promoting activity of Bcr/Abl, the causal oncoprotein for CML. When transformed with p210 Bcr/Abl, ICSBP-/- myeloid progenitor cells lost growth factor dependence and grew in the absence of granulocyte macrophage-colony stimulating factor. When ICSBP was ectopically expressed, Bcr/Abl-transformed cells underwent complete growth arrest and differentiated into mature, functional macrophages without inhibiting the kinase activity of Bcr/Abl. Providing a mechanistic basis for the growth arrest, ICSBP markedly repressed c-Myc mRNA expression, a downstream target of Bcr/Abl. A further analysis with the ICSBP/estrogen receptor chimera showed that ICSBP repression of c-Myc is indirect, and is mediated by another gene(s). We identified Blimp-1 and METS/PE1, potent c-Myc repressors, as direct targets of ICSBP activated in these cells. Consistent with this, ectopic Blimp-1 repressed c-Myc expression and inhibited cell growth. These results indicate that ICSBP inhibits growth of Bcr/Abl-transformed myeloid progenitor cells by activating several genes that interfere with the c-Myc pathway.
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