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Molecular and Cellular Biology, December 2001, p. 8129-8142, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.8129-8142.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

8p12 Stem Cell Myeloproliferative Disorder: the FOP-Fibroblast Growth Factor Receptor 1 Fusion Protein of the t(6;8) Translocation Induces Cell Survival Mediated by Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt/mTOR Pathways

Géraldine Guasch, Vincent Ollendorff,dagger Jean-Paul Borg, Daniel Birnbaum, and Marie-Josèphe Pébusque*

Laboratoire d'Oncologie Moléculaire, INSERM U 119, IFR 57, Marseille, France

Received 2 April 2001/Returned for modification 25 May 2001/Accepted 20 August 2001

The FOP-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell myeloproliferative disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of FOP to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of FOP-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing FOP-FGFR1. The survival function of FOP-FGFR1 is abrogated by mutation of the phospholipase C gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in FOP-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that FOP-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that FOP-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition, FOP-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by FOP-FGFR1. Finally, FOP-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of FOP-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.

* Corresponding author. Present address: INSERM-EMI 0116, Parc Scientifique et Technologique de Luminy, B.P. 172, 13276 Marseille Cedex 09, France. Phone: 33 4 91 82 75 42. Fax: 33 4 91 82 60 83. E-mail: pebusque{at}inserm-adr.univ-mrs.fr.

dagger Present address: Institut méditerranéen de recherche en nutrition, Marseille, France.

Molecular and Cellular Biology, December 2001, p. 8129-8142, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.8129-8142.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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