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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3778-3783
Number of pages6
JournalBlood
Volume98
Issue number13
DOIs
StatePublished - Dec 15 2001

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Receptor, Fibroblast Growth Factor, Type 1
Electric fuses
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Fusion reactions
Proteins
Polymerase chain reaction
Transcription
Fluorescence In Situ Hybridization
L 744832
Reverse Transcription
Exons
Growth
Genes
Fluorescence
Phosphatidylinositol 3-Kinase
Leukemia, Myeloid, Chronic Phase
Farnesyltranstransferase
Myeloproliferative Disorders
Polymerase Chain Reaction
Phosphorylation

ASJC Scopus subject areas

  • Hematology

Cite this

Demiroglu, A., Joanna Steer, E., Heath, C., Taylor, K., Bentley, M., Allen, S. L., ... Cross, N. 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. https://doi.org/10.1182/blood.V98.13.3778

The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1 : Transforming activity and specific inhibition of FGFR1 fusion proteins. / Demiroglu, Asuman; Joanna Steer, E.; 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.; Cross, Nicholas C P.

In: Blood, Vol. 98, No. 13, 15.12.2001, p. 3778-3783.

Research output: Contribution to journalArticle

Demiroglu, A, Joanna Steer, E, Heath, C, Taylor, K, Bentley, M, Allen, SL, Koduru, P, Brody, JP, Hawson, G, Rodwell, R, Doody, ML, Carnicero, F, Reiter, A, Goldman, JM, Melo, JV & Cross, NCP 2001, 'The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: Transforming activity and specific inhibition of FGFR1 fusion proteins', Blood, vol. 98, no. 13, pp. 3778-3783. https://doi.org/10.1182/blood.V98.13.3778
Demiroglu, Asuman ; Joanna Steer, E. ; 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. ; Cross, Nicholas C P. / The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1 : Transforming activity and specific inhibition of FGFR1 fusion proteins. In: Blood. 2001 ; Vol. 98, No. 13. pp. 3778-3783.
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AU - Taylor, Kerry

AU - Bentley, Mark

AU - Allen, Steven L.

AU - Koduru, Prasad

AU - Brody, Judith P.

AU - Hawson, Geoffrey

AU - Rodwell, Robyn

AU - Doody, Mary Lou

AU - Carnicero, Fernando

AU - Reiter, Andreas

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N2 - 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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