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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4142-4149. Prepublished online as a Blood First Edition Paper on February 19, 2004; DOI 10.1182/blood-2003-01-0285. This Article Full Text (PDF) All Versions of this Article: 2003-01-0285v1 103/11/4142    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Schmidt, M. Articles by Wolff, L. Search for Related Content PubMed PubMed Citation Articles by Schmidt, M. Articles by Wolff, L. Social Bookmarking                   What's this? Submitted January 29, 2003 Accepted February 9, 2004 The Interferon Regulatory Factor ICSBP/IRF8 in Combination with PU.1 Up-Regulates p15INK4b Tumor Suppressor Expression in Murine Myeloid Cells Martina Schmidt, Juraj Bies, Tomohiko Tamura, Keiko Ozato, and Linda Wolff* Laboratory of Cellular Oncology, NIH/NCI, Bethesda, MD, USA Laboratory of Molecular Growth Regulation, NIH/ NICHD, Bethesda, MD, USA * Corresponding author; email: LWOLFF{at}helix.nih.gov. CDKN2B (INK4B), which encodes the cyclin-dependent kinase inhibitor, p15INK4b, is up-regulated by many cytokines found in hematopoietic environments in vivo. In human acute myeloid leukemias (AML) it is inactivated with high frequency. To gain insight into the regulatory pathways leading to the normal activation of p15Ink4b expression, we examined interferon (IFN)-induced transcription. Using reporter gene assays in murine myeloid cells M1, we determined that a 328bp fragment, located 117bp upstream of the translation initiation site, was sufficient to activate transcription. Both, the interferon consensus sequence binding protein (ICSBP)/IRF-8 and PU.1 were able to increase transcription from this region. It was determined that both ICSBP and PU.1 must bind to DNA to form a stable PU.1/ICSBP binding complex. Interestingly, introduction of the ICSBP into ICSBP null Tot2 cells led to a significant increase in p15Ink4b RNA expression. This regulation of the Ink4b promoter is apparently myeloid-specific, because both ICSBP and PU.1 are myeloid commitment factors. Importantly, this provides a mechanism to explain in part the tumor suppressor activity of ICSBP, since ICSBP-deficient mice develop a chronic myelogenous leukemia (CML)-like disease and a high percentage of human AML and CML lack ICSBP transcripts. 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