A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome

Jan Cools, Daniel J. DeAngelo, Jason Gotlib, Elizabeth H. Stover, Robert D. Legare, Jorges Cortes, Jeffrey Kutok, Jennifer Clark, Ilene Galinsky, James D. Griffin, Nicholas C P Cross, Ayalew Tefferi, James Malone, Rafeul Alam, Stanley L. Schrier, Janet Schmid, Michal Rose, Peter Vandenberghe, Gregor Verhoef, Marc Boogaerts & 6 others Iwona Wlodarska, Hagop Kantarjian, Peter Marynen, Steven E. Coutre, Richard Stone, D. Gary Gilliland

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause. METHODS: We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response. RESULTS: Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRα (PDGFRA) gene generated by an interstitial deletion or chromosome 4q12. FIP1L1-PDGFRα is a constitutively activated tyrosine kinase thai transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib. CONCLUSIONS: The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase FIP1L1-PDGFRα - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRα is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.

Original languageEnglish (US)
Pages (from-to)1201-1214
Number of pages14
JournalNew England Journal of Medicine
Volume348
Issue number13
DOIs
StatePublished - Mar 27 2003

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Hypereosinophilic Syndrome
Protein-Tyrosine Kinases
Platelet-Derived Growth Factor Receptors
Genes
Therapeutics
Recurrence
Chromosome Deletion
Mutation
Imatinib Mesylate
Gene Fusion
Eosinophilia
Eosinophils
Chromosome Aberrations
Inhibitory Concentration 50
Phosphotransferases

ASJC Scopus subject areas

  • Medicine(all)

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A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. / Cools, Jan; DeAngelo, Daniel J.; Gotlib, Jason; Stover, Elizabeth H.; Legare, Robert D.; Cortes, Jorges; Kutok, Jeffrey; Clark, Jennifer; Galinsky, Ilene; Griffin, James D.; Cross, Nicholas C P; Tefferi, Ayalew; Malone, James; Alam, Rafeul; Schrier, Stanley L.; Schmid, Janet; Rose, Michal; Vandenberghe, Peter; Verhoef, Gregor; Boogaerts, Marc; Wlodarska, Iwona; Kantarjian, Hagop; Marynen, Peter; Coutre, Steven E.; Stone, Richard; Gilliland, D. Gary.

In: New England Journal of Medicine, Vol. 348, No. 13, 27.03.2003, p. 1201-1214.

Research output: Contribution to journalArticle

Cools, J, DeAngelo, DJ, Gotlib, J, Stover, EH, Legare, RD, Cortes, J, Kutok, J, Clark, J, Galinsky, I, Griffin, JD, Cross, NCP, Tefferi, A, Malone, J, Alam, R, Schrier, SL, Schmid, J, Rose, M, Vandenberghe, P, Verhoef, G, Boogaerts, M, Wlodarska, I, Kantarjian, H, Marynen, P, Coutre, SE, Stone, R & Gilliland, DG 2003, 'A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome', New England Journal of Medicine, vol. 348, no. 13, pp. 1201-1214. https://doi.org/10.1056/NEJMoa025217
Cools, Jan ; DeAngelo, Daniel J. ; Gotlib, Jason ; Stover, Elizabeth H. ; Legare, Robert D. ; Cortes, Jorges ; Kutok, Jeffrey ; Clark, Jennifer ; Galinsky, Ilene ; Griffin, James D. ; Cross, Nicholas C P ; Tefferi, Ayalew ; Malone, James ; Alam, Rafeul ; Schrier, Stanley L. ; Schmid, Janet ; Rose, Michal ; Vandenberghe, Peter ; Verhoef, Gregor ; Boogaerts, Marc ; Wlodarska, Iwona ; Kantarjian, Hagop ; Marynen, Peter ; Coutre, Steven E. ; Stone, Richard ; Gilliland, D. Gary. / A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. In: New England Journal of Medicine. 2003 ; Vol. 348, No. 13. pp. 1201-1214.
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abstract = "BACKGROUND: Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause. METHODS: We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response. RESULTS: Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRα (PDGFRA) gene generated by an interstitial deletion or chromosome 4q12. FIP1L1-PDGFRα is a constitutively activated tyrosine kinase thai transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib. CONCLUSIONS: The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase FIP1L1-PDGFRα - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRα is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.",
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T1 - A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome

AU - Cools, Jan

AU - DeAngelo, Daniel J.

AU - Gotlib, Jason

AU - Stover, Elizabeth H.

AU - Legare, Robert D.

AU - Cortes, Jorges

AU - Kutok, Jeffrey

AU - Clark, Jennifer

AU - Galinsky, Ilene

AU - Griffin, James D.

AU - Cross, Nicholas C P

AU - Tefferi, Ayalew

AU - Malone, James

AU - Alam, Rafeul

AU - Schrier, Stanley L.

AU - Schmid, Janet

AU - Rose, Michal

AU - Vandenberghe, Peter

AU - Verhoef, Gregor

AU - Boogaerts, Marc

AU - Wlodarska, Iwona

AU - Kantarjian, Hagop

AU - Marynen, Peter

AU - Coutre, Steven E.

AU - Stone, Richard

AU - Gilliland, D. Gary

PY - 2003/3/27

Y1 - 2003/3/27

N2 - BACKGROUND: Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause. METHODS: We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response. RESULTS: Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRα (PDGFRA) gene generated by an interstitial deletion or chromosome 4q12. FIP1L1-PDGFRα is a constitutively activated tyrosine kinase thai transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib. CONCLUSIONS: The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase FIP1L1-PDGFRα - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRα is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.

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U2 - 10.1056/NEJMoa025217

DO - 10.1056/NEJMoa025217

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JF - New England Journal of Medicine

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