A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome

Salemi, S; Yousefi, S; Simon, D; Schmid, I; Moretti, L; Scapozza, L; Simon, H-U (2009). A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome. Allergy, 64(6), pp. 913-8. Oxford: Wiley-Blackwell 10.1111/j.1398-9995.2009.01943.x

Full text not available from this repository. (Request a copy)

BACKGROUND: The Fip1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) gene fusion is a common cause of chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES), and patients suffering from this particular subgroup of CEL/HES respond to low-dose imatinib therapy. However, some patients may develop imatinib resistance because of an acquired T674I mutation, which is believed to prevent drug binding through steric hindrance. METHODS: In an imatinib resistant FIP1L1-PDGFRA positive patient, we analyzed the molecular structure of the fusion gene and analyzed the effect of several kinase inhibitors on FIP1L1-PDGFRA-mediated proliferative responses in vitro. RESULTS: Sequencing of the FIP1L1-PDGFRA fusion gene revealed the occurrence of a S601P mutation, which is located within the nucleotide binding loop. In agreement with the clinical observations, imatinib did not inhibit the proliferation of S601P mutant FIP1L1-PDGFRA-transduced Ba/F3 cells. Moreover, sorafenib, which has been described to inhibit T674I mutant FIP1L1-PDGFRA, failed to block S601P mutant FIP1L1-PDGFRA. Structural modeling revealed that the newly identified S601P mutated form of PDGFRA destabilizes the inactive conformation of the kinase domain that is necessary to bind imatinib as well as sorafenib. CONCLUSIONS: We identified a novel mutation in FIP1L1-PDGFRA resulting in both imatinib and sorafenib resistance. The identification of novel drug-resistant FIP1L1-PDGFRA variants may help to develop the next generation of target-directed compounds for CEL/HES and other leukemias.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Dermatology

UniBE Contributor:

Yousefi, Shida; Simon, Dagmar and Simon, Hans-Uwe

ISSN:

0105-4538

ISBN:

19210352

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Aline Kunz

Date Deposited:

04 Oct 2013 15:09

Last Modified:

10 Feb 2017 15:27

Publisher DOI:

10.1111/j.1398-9995.2009.01943.x

PubMed ID:

19210352

Web of Science ID:

000265980900012

URI:

https://boris.unibe.ch/id/eprint/30400 (FactScience: 193787)

Actions (login required)

Edit item Edit item
Provide Feedback