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The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins

The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins
The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins
This report describes 2 patients with a clinical and hematologic diagnosis of chronic myeloid leukemia (CML) in chronic phase who had an acquired t(8;22)(p11;q11). Analysis by fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR) indicated that both patients were negative for the BCR-ABL fusion, but suggested that the BCR gene was disrupted. Further FISH indicated a breakpoint within fibroblast growth factor receptor 1 (FGFR1), the receptor tyrosine kinase that is known to be disrupted in a distinctive myeloproliferative disorder, most commonly by fusion to ZNF198. RT-PCR confirmed the presence in both cases of an in-frame messenger RNA fusion between BCR exon 4 and FGFR1 exon 9. Expression of BCR-FGFR1 in the factor-dependent cell line Ba/F3 resulted in interleukin 3-independent clones that grew at a comparable rate to cells transformed with ZNF198-FGFR1. The growth of transformed cells was inhibited by the phosphatidylinositol 3-kinase inhibitor LY294002, the farnesyltransferase inhibitors L744832 and manumycin A, the p38 inhibitors SB202190 and SB203580 but not by the MEK inhibitor PD98059. The growth of BaF3/BCR-FGFR1 and BaF3/ZNF198-FGFR1 was not significantly inhibited by treatment with STI571, but was inhibited by SU5402, a compound with inhibitory activity against FGFR1. Inhibition with this compound was associated with decreased phosphorylation of ERK1/2 and BCR-FGFR1 or ZNF198-FGFR1, and was dose dependent with an inhibitory concentration of 50% of approximately 5 µM. As expected, growth of BaF3/BCR-ABL was inhibited by STI571 but not by SU5402. The study demonstrates that the BCR-FGFR1 fusion may occur in patients with apparently typical CML. Patients with constitutively active FGFR1 fusion genes may be amenable to treatment with specific FGFR1 inhibitors.
0006-4971
3778-3783
Demiroglu, Asuman
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Steer, E. Joanna
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Heath, Carol
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Taylor, Kerry
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Bentley, Mark
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Allen, Steven L.
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Koduru, Prasad
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Brody, Judith P.
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Hawson, Geoffrey
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Rodwell, Robyn
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Doody, Mary Lou.
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Carnicero, Fernando
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Reiter, Andreas
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Goldman, John M.
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Melo, Junia V.
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Cross, Nicholas C.P.
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Demiroglu, Asuman
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Steer, E. Joanna
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Heath, Carol
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Taylor, Kerry
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Bentley, Mark
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Allen, Steven L.
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Koduru, Prasad
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Brody, Judith P.
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Hawson, Geoffrey
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Rodwell, Robyn
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Doody, Mary Lou.
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Carnicero, Fernando
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Reiter, Andreas
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Goldman, John M.
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Melo, Junia V.
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Cross, Nicholas C.P.
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Demiroglu, Asuman, Steer, E. Joanna, Heath, Carol, Taylor, Kerry, Bentley, Mark, Allen, Steven L., Koduru, Prasad, Brody, Judith P., Hawson, Geoffrey, Rodwell, Robyn, Doody, Mary Lou., Carnicero, Fernando, Reiter, Andreas, Goldman, John M., Melo, Junia V. and Cross, Nicholas C.P. (2001) The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins. Blood, 98 (13), 3778-3783. (doi:10.1182/blood.V98.13.3778).

Record type: Article

Abstract

This report describes 2 patients with a clinical and hematologic diagnosis of chronic myeloid leukemia (CML) in chronic phase who had an acquired t(8;22)(p11;q11). Analysis by fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR) indicated that both patients were negative for the BCR-ABL fusion, but suggested that the BCR gene was disrupted. Further FISH indicated a breakpoint within fibroblast growth factor receptor 1 (FGFR1), the receptor tyrosine kinase that is known to be disrupted in a distinctive myeloproliferative disorder, most commonly by fusion to ZNF198. RT-PCR confirmed the presence in both cases of an in-frame messenger RNA fusion between BCR exon 4 and FGFR1 exon 9. Expression of BCR-FGFR1 in the factor-dependent cell line Ba/F3 resulted in interleukin 3-independent clones that grew at a comparable rate to cells transformed with ZNF198-FGFR1. The growth of transformed cells was inhibited by the phosphatidylinositol 3-kinase inhibitor LY294002, the farnesyltransferase inhibitors L744832 and manumycin A, the p38 inhibitors SB202190 and SB203580 but not by the MEK inhibitor PD98059. The growth of BaF3/BCR-FGFR1 and BaF3/ZNF198-FGFR1 was not significantly inhibited by treatment with STI571, but was inhibited by SU5402, a compound with inhibitory activity against FGFR1. Inhibition with this compound was associated with decreased phosphorylation of ERK1/2 and BCR-FGFR1 or ZNF198-FGFR1, and was dose dependent with an inhibitory concentration of 50% of approximately 5 µM. As expected, growth of BaF3/BCR-ABL was inhibited by STI571 but not by SU5402. The study demonstrates that the BCR-FGFR1 fusion may occur in patients with apparently typical CML. Patients with constitutively active FGFR1 fusion genes may be amenable to treatment with specific FGFR1 inhibitors.

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Published date: 15 December 2001

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Local EPrints ID: 24682
URI: https://eprints.soton.ac.uk/id/eprint/24682
ISSN: 0006-4971
PURE UUID: baee8a4f-75b3-41d4-a4d6-bc2f3faeb489
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 03 Apr 2006
Last modified: 06 Jun 2018 12:49

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Contributors

Author: Asuman Demiroglu
Author: E. Joanna Steer
Author: Carol Heath
Author: Kerry Taylor
Author: Mark Bentley
Author: Steven L. Allen
Author: Prasad Koduru
Author: Judith P. Brody
Author: Geoffrey Hawson
Author: Robyn Rodwell
Author: Mary Lou. Doody
Author: Fernando Carnicero
Author: Andreas Reiter
Author: John M. Goldman
Author: Junia V. Melo

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