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J. Biol. Chem., Vol. 282, Issue 8, 5633-5640, February 23, 2007

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Interferon Regulatory Factor-8 Is Indispensable for the Expression of Promyelocytic Leukemia and the Formation of Nuclear Bodies in Myeloid Cells^*

Natalie Dror, Naama Rave-Harel, Andreas Burchert, Aviva Azriel, Tomohiko Tamura^¶, Prafullakumar Tailor^¶, Andreas Neubauer, Keiko Ozato^¶, and Ben-Zion Levi¹

From the Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel, Universitätsklinikum Marburg und Giessen, Standort Marburg, Klinik für Hämatologie, Onkologie, D-35033 Marburg, Germany, and ^¶Laboratory of Molecular Growth Regulation, NICHD, National Institutes of Health, Bethesda, Maryland 20892

Interferon (IFN) regulatory factor-8 (IRF-8), previously known as ICSBP, is a myeloid cell essential transcription factor. Mice with null mutation in IRF-8 are defective in the ability of myeloid progenitor cells to mature toward macrophage lineage. Accordingly, these mice develop chronic myelogenous leukemia (CML). We demonstrate here that IRF-8 is an obligatory regulator of the promyelocytic leukemia (PML) gene in activated macrophages, leading to the expression of the PML-I isoform. This regulation is most effective together with two other transcription factors, IRF-1 and PU.1. PML is a tumor suppressor gene that serves as a scaffold protein for nuclear bodies. IRF-8 is not only essential for the IFN--induced expression of PML in activated macrophages but also for the formation of nuclear bodies. Reduced IRF-8 transcript levels were reported in CML patients, and a recovery to normal levels was observed in patients in remission following treatment with IFN-. We demonstrate a significant correlation between the levels of IRF-8 and PML in these CML patients. Together, our results indicate that some of the myeloleukemia suppressor activities of IRF-8 are mediated through the regulation of PML. When IRF-8 levels are compromised, the reduced PML expression may lead to genome instability and eventually to the leukemic phenotype.

Received for publication, August 16, 2006 , and in revised form, December 5, 2006.

^* This work was supported in part by Israel Science Foundation Grant 536/01, by the fund for the promotion of research at the Technion (to B.-Z. L.), by the José Carreras Leukämie Stiftung (to A. B.), and by the Deutsche Forschungsgemeinschaft (to A. B. and A. N.). B. Z. Levi is an incumbent of the Lily and Silvian Marcus Chain in Life Sciences at the Technion. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 972-4-8293345; Fax: 972-4-8293399; E-mail: blevi{at}technion.ac.il.

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