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Oncogenes, Fusion Genes and Tumor Suppressor Genes

Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1

Leukemia volume 23, pages 358–364 (2009)Cite this article

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.

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Acknowledgements

Research supported by Leukaemia Research, UK.

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Authors and Affiliations

  1. Salisbury and Human Genetics Division, Wessex Regional Genetics Laboratory, University of Southampton, Southampton, UK

    A Chase, S Kreil, J Baxter, C Hidalgo-Curtis, A Jones, L Zhang, F H Grand & N C P Cross

  2. Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK

    B Schultheis & J V Melo

  3. Department of Haematology, Institute of Medical & Veterinary Science, University of Adelaide, Adelaide, South Australia, Australia

    J V Melo

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  1. A Chase
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Correspondence to A Chase.

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Chase, A., Schultheis, B., Kreil, S. et al. Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1. Leukemia 23, 358–364 (2009). https://doi.org/10.1038/leu.2008.295

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