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

Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1
Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1
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
GDM1, CSF1R, tyrosine kinase
0887-6924
358-364
Chase, A.
a40a09c2-3073-4655-ba0b-a802e34914b5
Schultheis, B.
98496e70-2fd8-4076-bda0-b0017cf96cc7
Kreil, S.
2404ac13-cdaa-43a3-913b-adceb79e598f
Baxter, J.
f9c3d01c-67d8-4b71-bb1b-c673be462672
Hidalgo-Curtis, C.
b492ffa5-2adb-4901-973f-72e2432b0ee0
Jones, A.
bcae84a4-4191-4a3e-b695-1b6e2b0681c7
Zhang, L.
1170f035-b8d0-490c-ac24-ee05105011a7
Grand, F.H.
f4b9e5f4-28c4-44d2-9916-d852c2fdaef8
Melo, J.V.
e3ef7550-b67a-458c-af81-5d7dd8fb1306
Cross, N.C.
f87650da-b908-4a34-b31b-d62c5f186fe4
Chase, A.
a40a09c2-3073-4655-ba0b-a802e34914b5
Schultheis, B.
98496e70-2fd8-4076-bda0-b0017cf96cc7
Kreil, S.
2404ac13-cdaa-43a3-913b-adceb79e598f
Baxter, J.
f9c3d01c-67d8-4b71-bb1b-c673be462672
Hidalgo-Curtis, C.
b492ffa5-2adb-4901-973f-72e2432b0ee0
Jones, A.
bcae84a4-4191-4a3e-b695-1b6e2b0681c7
Zhang, L.
1170f035-b8d0-490c-ac24-ee05105011a7
Grand, F.H.
f4b9e5f4-28c4-44d2-9916-d852c2fdaef8
Melo, J.V.
e3ef7550-b67a-458c-af81-5d7dd8fb1306
Cross, N.C.
f87650da-b908-4a34-b31b-d62c5f186fe4

Chase, A., Schultheis, B., Kreil, S., Baxter, J., Hidalgo-Curtis, C., Jones, A., Zhang, L., Grand, F.H., Melo, J.V. and Cross, N.C. (2009) Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1. Leukemia, 23 (2), 358-364. (doi:10.1038/leu.2008.295).

Record type: 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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Published date: February 2009
Keywords: GDM1, CSF1R, tyrosine kinase

Identifiers

Local EPrints ID: 69553
URI: https://eprints.soton.ac.uk/id/eprint/69553
ISSN: 0887-6924
PURE UUID: ff542129-f4c9-4b85-bfad-393b7e9bad3d
ORCID for N.C. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 18 Nov 2009
Last modified: 06 Jun 2018 12:49

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Contributors

Author: A. Chase
Author: B. Schultheis
Author: S. Kreil
Author: J. Baxter
Author: C. Hidalgo-Curtis
Author: A. Jones
Author: L. Zhang
Author: F.H. Grand
Author: J.V. Melo
Author: N.C. Cross ORCID iD

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