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Ref Type Journal Article
PMID (18971950)
Authors Chase A, Schultheis B, Kreil S, Baxter J, Hidalgo-Curtis C, Jones A, Zhang L, Grand FH, Melo JV, Cross NC
Title Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1.
Journal Leukemia
Vol 23
Issue 2
Date 2009 Feb
Abstract Text 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.


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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
CSF1R D802V missense gain of function CSF1R D802V lies within the protein kinase domain of the Csf1r protein ( D802V confers a gain of function as demonstrated by increased stability of the Csf1r protein and the ability to transform cells in cultrue (PMID: 10340379, PMID: 18971950).
CSF1R Y571D missense gain of function CSF1R Y571D lies within the regulatory juxtamembrane domain of the Csf1r protein ( Y571D was shown to result in constitutive activation of the Csf1r protein, increased colony growth, and elevated Csf1r signaling in cultured cells (PMID: 18971950).
CSF1R Y969F missense gain of function - predicted CSF1R Y969F lies within the cytoplasmic domain of the Csf1r protein ( Y969F has not been biochemically characterized, but results in increased transforming ability compared to wild-type Csf1r protein in cell culture (PMID: 18971950) and therefore, is predicted to result in a gain of Csf1r protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CSF1R Y571D myeloid leukemia sensitive Imatinib Preclinical Actionable In a preclinical study, CSFR1 Y571D conferred sensitivity to Gleevec (imatinib) in myeloid cell lines in culture (PMID: 18971950). 18971950