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Hématologie

A distinct clinical entity of myeloproliferative disorders: the 8p12 myeloproliferative syndrome associated with FGFR1 gene Volume 9, issue 1, Janvier - Février 2003

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We report a distinct atypical stem cell myeloproliferative disorder (MPD) characterized by recurrent translocations involving the short arm of chromosome 8, region 8p12. This disease has similarities with chronic myeloid leukemia but is associated with myeloid hyperplasia, eosinophilia, and very often with high grade non Hodgkin's lymphoma of either B-or, more commonly, T-cell phenotype. This disease is aggressive and rapidly transforms to acute myeloid leukemia, usually of myeloid phenotype. To date, only allogenic stem cell transplantation appears to be effective in eradicating or suppressing the malignant clone. The hallmark of the 8p12 SMP is the diruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. To date, five fusion genes associated with different translocations have been identified and cloned: FOP (6q27), CEP110 (9q33), FIM/RAMP/ZNF198 (13q12), HERV-K (19q13.3), and BCR (22q11). In each case, the N-terminal region of the partner, which contains domains allowing protein-protein interaction, is fused to the tyrosine kinase domain of FGFR1. We have recently shown that the fusion proteins X-FGFR1 are abnormally localized to the cytoplasm and constitutively activated upon dimerization, mediated by the N-terminal portion of the FGFR1 partner. They protect cells from apoptosis through connection with intricated signaling pathways. This mechanism contributes to the neoplasic behaviour.of 8p12 MPD, a novel distinct clinical identity caused by constitutive activation of FGFR1. These pathways and the fusion proteins are attractive candidates for targeted signal transduction therapy.