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J. Biol. Chem., Vol. 279, Issue 8, 6666-6673, February 20, 2004

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Critical Role of STAT5 Activation in Transformation Mediated by ZNF198-FGFR1^*

Carol Heath and Nicholas C. P. Cross¶

From the Department of Haematology, Imperial College Faculty of Medicine, Hammersmith Hospital, W12 ONN London and Wessex Regional Genetics Laboratory, Salisbury SP2 8BJ and Human Genetics Division, University of Southampton School of Medicine, Southampton, SO16 6YD United Kingdom

The 8p11 myeloproliferative syndrome is an aggressive disorder caused by FGFR1 fusion proteins resulting from a subset of acquired translocations that target chromosome band 8p11. These chimeric proteins have constitutive FGFR1 tyrosine kinase activity and are believed to deregulate hemopoietic development in a manner analogous to BCR-ABL in chronic myeloid leukemia. Here we have studied the role of STAT proteins in transformation mediated by the most common of these fusions, ZNF198-FGFR1. We found that STATs 1, 3, and 5 were activated constitutively in ZNF198-FGFR1-transformed Ba/F3 cells and that STATs 2, 4, and 6 were also tyrosine-phosphorylated. Induction of dominant negative STAT mutants showed that activation of STAT5, but not STATs 1 or 3, was essential for the anti-apoptotic effect of ZNF198-FGFR1 and that STAT5 activation is essential for the elevated levels of BclXL in transformed cells. STAT5 activation was also shown to be required for continued cell cycle progression of BaF3/ZNF198-FGFR1 cells in conditions of cytokine deprivation and for up-regulation of the DNA repair protein Rad51. These findings suggest a critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1.

Received for publication, August 7, 2003 , and in revised form, November 26, 2003.

^* This work was supported by the Leukemia Research Fund. 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.

^¶ To whom correspondence should be addressed: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK. Tel.: 44-1722-429080; Fax: 44-1722-338095; E-mail: ncpc{at}soton.ac.uk.

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