title: Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1.
abstract: Imatinib is usually a highly effective treatment for myeloproliferative neoplasms (MPNs) associated with ABL, PDGFRA or PDGFRB gene fusions; however, occasional imatinib-responsive patients have been reported without abnormalities of these genes. To identify novel imatinib-sensitive lesions, we screened 11 BCR-ABL-negative cell lines and identified GDM1, derived from a patient with an atypical MPN (aMPN), as being responsive to imatinib. Screening of genes encoding known imatinib targets revealed an exon 12 mutation in the colony-stimulating factor 1 receptor (CSF1R; c-FMS) with a predicted Y571D amino-acid substitution. CSF1R in GDM1 was constitutively phosphorylated, but rapidly dephosphorylated on exposure to imatinib. Y571D did not transform FDCP1 cells to growth factor independence, but resulted in a significantly increased colony growth compared with controls, constitutive CSF1R phosphorylation and elevated CSF1R signaling. We found that GDM1 expresses CSF1, and CSF1 neutralization partially inhibited proliferation, suggesting the importance of both autocrine and intrinsic mechanisms of CSF1R activation. An extensive screen of CSF1R in aMPNs and acute myeloid leukemia identified three additional novel missense variants. None of these variants were active in transformation assays and are therefore likely to be previously unreported rare polymorphisms or non-pathogenic passenger mutations.
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury and Human Genetics Division, University of Southampton, Southampton, UK. achase@soton.ac.uk
authors.forename: A
authors.initials: A
authors.lastname: Chase
authors.forename: B
authors.initials: B
authors.lastname: Schultheis
authors.forename: S
authors.initials: S
authors.lastname: Kreil
authors.forename: J
authors.initials: J
authors.lastname: Baxter
authors.forename: C
authors.initials: C
authors.lastname: Hidalgo-Curtis
authors.forename: A
authors.initials: A
authors.lastname: Jones
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: F H
authors.initials: FH
authors.lastname: Grand
authors.forename: J V
authors.initials: JV
authors.lastname: Melo
authors.forename: N C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D001549:Benzamides; D045744:Cell Line, Tumor; D006801:Humans; D000068877:Imatinib Mesylate; D016173:Macrophage Colony-Stimulating Factor; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D016173:Macrophage Colony-Stimulating Factor; D000068877:Imatinib Mesylate; D016186:Receptor, Macrophage Colony-Stimulating Factor