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).
|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)]|
|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|
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