Reactome: A Curated Pathway Database

Signaling by FGFR1 fusion mutants (R-HSA-1839117)

Species Homo sapiens


8p11 myeloproliferative syndrome (EMS) is an aggressive disorder that is associated with a translocation event at the FGFR1 gene on chromosome 8p11. Typical symptoms upon diagnosis include eosinophilia and associated T-cell lymphoblastic lymphoma; the disease rapidly advances to acute leukemia, usually of myeloid lineage. At present the only effective treatment is allogenic stem cell transplantation (reviewed in Jackson, 2010).

At the molecular level, EMS appears to be caused by translocation events on chromosome 8 that create gene fusions between the intracellular domain of FGFR1 and an N-terminal partner gene that encodes a dimerization domain. The resulting fusion protein dimerizes in a ligand-independent fashion based the N-terminal domain provided by the partner protein and stimulates constititutive downstream FGFR1 signaling without altering the intrisic kinase activity of the receptor. To date, 11 partner genes have been identified: ZMYM2, FGFR1OP, FGFR1OP2, HERVK, TRIM24, CUX1, BCR, CEP110, LRRFIP1, MYO18A and CPSF6, although not all have been functionally characterized (reviewed in Jackson, 2010, Turner and Grose, 2010; Wesche, 2011).
Where examined, cell lines carrying FGFR1 fusion genes have been shown to be transforming and to support IL3-independent proliferation through anti-apoptotic, prosurvival pathways(Lelievre, 2008; Ollendorff, 1999; Chase, 2007; Guasch, 2001; Wasag 2011; Roumiantsev, 2004; Demiroglu, 2001; Smedley, 1999). Signaling appears to occur predominantly through PLCgamma, PI3K and STAT signaling, with a more minor contribution from MAPK activation. Because the fusion proteins lack the FRS2-binding site, the mechanism of MAPK activation is unclear. Recruitment of GRB2:SOS1 through recruitment of SHC is one possibility (Guasch, 2001).

Locations in the PathwayBrowser
Additional Information
Compartment cytosol
Name Identifier Synonyms
chronic myeloid leukemia 8552 [CML, chronic myelogenous leukemia, no ICD-O subtype (morphologic abnormality), chronic myeloid leukemia, disease (disorder), chronic myeloid leukemia without mention of remission, CML - chronic Myelogenous Leukemia, chronic myeloid leukemia in remission (disorder), Myeloid Leukemia, chronic, CML in Remission, chronic myeloid leukemia in remission, chronic myeloid leukaemia, chronic myeloid leukemia NOS (disorder)]
subacute leukemia 3264
myelodysplastic myeloproliferative cancer 4972 [Myeloproliferative/Myelodysplastic syndromes, unclassifiable myelodysplastic myeloproliferative disease, Unclassifiable Myeloproliferative/Myelodysplastic syndrome, Myelodysplastic/myeloproliferative disease (morphologic abnormality)]
precursor lymphoblastic lymphoma/leukemia 5600
Literature References
pubMedId Title Journal Year
21367659 Targeting mutant fibroblast growth factor receptors in cancer Trends Mol Med 2011
20094046 Fibroblast growth factor signalling: from development to cancer Nat Rev Cancer 2010
20226962 8p11 myeloproliferative syndrome: a review Hum Pathol 2010
18412956 Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cgamma at the centrosome Mol Cancer 2008
10480903 Characterization of FIM-FGFR1, the fusion product of the myeloproliferative disorder-associated t(8;13) translocation J Biol Chem 1999
17698633 Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome Blood 2007
11689702 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 Mol Cell Biol 2001
21330321 The kinase inhibitor TKI258 is active against the novel CUX1-FGFR1 fusion detected in a patient with T-lymphoblastic leukemia/lymphoma and t(7;8)(q22;p11) Haematologica 2011
15050920 Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations Cancer Cell 2004
11739186 The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins Blood 2001
10935490 ZNF198-FGFR1 transforms Ba/F3 cells to growth factor independence and results in high level tyrosine phosphorylation of STATS 1 and 5 Neoplasia 1999
21711248 Fibroblast growth factors and their receptors in cancer Biochem J 2011