A Tyrosine Kinase Created by Fusion of thePDGFRAandFIP1L1Genes as a Therapeutic Target of Imatinib in Idiopathic Hypereosinophilic Syndrome

Abstract

The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRalpha is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.

Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines

“…Therapeutic use of TKIs has been effective for patients with several leukaemias [44][45][46][47][48] . To determine the effect of PTK inhibition on CrkL phosphorylation and demonstrate the TKI inhibitor assessment potential of the approach, leukaemogenic PTK expressing cell lines were treated with IM and DAS (5 and 0.15µM respectively) for 5h.…”

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…A subset of patients with CEL have fusion of platelet-derived growth factor receptor-α (PDGFRα) to FIP1L1 (REF. 94), and an acquired point mutation (V617F) in the non-receptor tyrosine kinase Janus kinase 2 (JAK2) is found in most patients with PV and about half of patients with ET and chronic idiopathic myelofibrosis 95 .…”

New agents in acute myeloid leukemia and other myeloid disorders

“…In vitro studies of the effect of imatinib mesylate on the growth of Ba/F3 cells that expressed FIP1L1-PDGFR␣ showed that they were inhibited efficiently by much lower concentrations of imatinib than Ba/F3 cells that expressed BCR-ABL (50% inhibitory concentration, 3.2 nM vs. 582 nM, respectively). 50 It is noteworthy that a fraction of patients with HES respond to therapy with imatinib mesylate. 50,51 Responses can be achieved at a lower dose of imatinib (100 mg per day) than the dose used in patients with CML and can occur in the absence of a detectable FIP1L1-PDGFR␣ fusion, suggesting that other, as yet unidentified molecular abnormalities/mechanisms also may exist.…”

“…50 It is noteworthy that a fraction of patients with HES respond to therapy with imatinib mesylate. 50,51 Responses can be achieved at a lower dose of imatinib (100 mg per day) than the dose used in patients with CML and can occur in the absence of a detectable FIP1L1-PDGFR␣ fusion, suggesting that other, as yet unidentified molecular abnormalities/mechanisms also may exist. 50 3) Imatinib mesylate inhibits the catalytic activity of the receptor tyrosine kinase, c-kit, which is ex-pressed in Ͼ 90% of patients with AML.…”