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Oncogenic Tyrosine Kinase of Malignant Hemopathy Targets the Centrosome

Laboratories of ¹ Molecular Oncology and ² Molecular Hematopoiesis, Marseille Cancer Institute, UMR599 Inserm and Institut Paoli-Calmettes, Marseilles, France; ³ U366 Inserm, Grenoble; and ⁴ Hybrigenics S.A., Paris, France

Requests for reprints: Daniel Birnbaum, Laboratory of Molecular Oncology, Marseille Cancer Institute, UMR599 Inserm, 27 Bd. Leï Roure, 13009 Marseilles, France. Phone: 33-49175-8407; Fax: 33-49126-0364; E-mail: birnbaum{at}marseille.inserm.fr.

Myeloproliferative disorders (MPD) are malignant diseases of hematopoietic progenitor cells. Many MPDs result from a chromosomal translocation that creates a fusion gene encoding a chimeric kinase. The fibroblast growth factor receptor 1 (FGFR1)-MPD is characterized by the fusion of the FGFR1 kinase with various partners, including FOP. We show here that both normal FOP and FOP-FGFR1 fusion kinase localize to the centrosome. The fusion kinase encounters substrates at the centrosome where it induces strong phosphorylation on tyrosine residues. Treatment with FGFR1 kinase inhibitor SU5402 abolishes FOP-FGFR1-induced centrosomal phosphorylation and suppresses the proliferative and survival potentials of FOP-FGFR1 Ba/F3 cells. We further show that FOP-FGFR1 allows cells to overcome G₁ arrest. Therefore, the FOP-FGFR1 fusion kinase targets the centrosome, activates signaling pathways at this organelle, and sustains continuous entry in the cell cycle. This could represent a potential new mechanism of oncogenic transformation occurring specifically at the centrosome.

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