Comparative proteomic analysis of blood eosinophils reveals redox signaling modifications in patients with FIP1L1-PDGFRA-associated chronic eosinophilic leukemia.

Abstract

The FIP1L1-PDGFRA (F/P) fusion gene, which was identified as a recurrent molecular finding in hypereosinophilic syndrome (HES), lead to a constitutively increased tyrosine kinase activity of the fusion protein. Despite data obtained in animals or cell lines models, the mechanisms underlying the predominant eosinophil lineage targeting and the cytotoxicity of eosinophils in this leukemia remain unclear. To define more precisely intrinsic molecular events associated with F/P gene, we performed a proteomic analysis comparing F/P+ eosinophils (F/P-Eos) and eosinophils from healthy donors (C-Eos). Using 2D-DIGE and mass spectrometry techniques, we identified 41 proteins significantly overexpressed between F/P-Eos and C-Eos. Among them, 17.8% belonged to the oxidoreductase family. We further observed a down-expression of peroxiredoxin-2 (PRX-2) and an overexpression of src-homology-2 domain containing tyrosine phosphatase (SHP-1), enzymes regulating PDGFR downstream pathways, and especially intracellular reactive oxygen species (ROS) production. This profile, confirmed in immunoblot analysis, appears specific to F/P-Eos compared to controls and patients with idiopathic HES. In this clonal disorder possibly involving a pluripotent hematopoietic stem cell, we postulate that the well documented relationships between PDGFRA downstream signals and intracellular ROS levels might influence the phenotype of this leukemia.

• Authors: Jean-Emmanuel Kahn, Virginie Dutoit-Lefevre, Sophie Duban-Deweer, Philippe Chafey, Gwenael Pottiez, Didier Lefranc, Olivier Fain, Jean-Francois Cordier, Pierre-Yves Hatron, Olivier Bletry, Lionel Prin
• Journal: Journal of proteome research (J Proteome Res) Vol. 10 Issue 4 Pg. 1468-80 (Apr 01 2011) ISSN: 1535-3907 [Electronic] United States
• PMID: 21302907 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FIP1L1 protein, human
• Oncogene Proteins, Fusion
• Proteome
• Reactive Oxygen Species
• mRNA Cleavage and Polyadenylation Factors
• PRDX2 protein, human
• Peroxiredoxins
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Adult
• Aged
• Animals
• Cell Line
• Databases, Protein
• Eosinophils (chemistry, metabolism)
• Female
• Humans
• Hypereosinophilic Syndrome (genetics, metabolism, physiopathology)
• Male
• Mass Spectrometry (methods)
• Middle Aged
• Oncogene Proteins, Fusion (genetics, metabolism)
• Oxidation-Reduction
• Peroxiredoxins (genetics, metabolism)
• Proteome (analysis)
• Reactive Oxygen Species (metabolism)
• Receptor, Platelet-Derived Growth Factor alpha (genetics, metabolism)
• Signal Transduction (physiology)
• Two-Dimensional Difference Gel Electrophoresis (methods)
• mRNA Cleavage and Polyadenylation Factors (genetics, metabolism)