title: 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.affiliation: Service de Médecine Interne, Hôpital Foch, 40 rue Worth, 92151 Suresnes Cedex, France.
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Kahn
authors.forename: Virginie
authors.initials: V
authors.lastname: Dutoit-Lefevre
authors.forename: Sophie
authors.initials: S
authors.lastname: Duban-Deweer
authors.forename: Philippe
authors.initials: P
authors.lastname: Chafey
authors.forename: Gwenael
authors.initials: G
authors.lastname: Pottiez
authors.forename: Didier
authors.initials: D
authors.lastname: Lefranc
authors.forename: Olivier
authors.initials: O
authors.lastname: Fain
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Cordier
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Hatron
authors.forename: Olivier
authors.initials: O
authors.lastname: Bletry
authors.forename: Lionel
authors.initials: L
authors.lastname: Prin
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D030562:Databases, Protein; D004804:Eosinophils / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism; D020543:Proteome / Q000032:analysis*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D057825:Two-Dimensional Difference Gel Electrophoresis / Q000379:methods; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C479818:FIP1L1 protein, human; D015514:Oncogene Proteins, Fusion; D020543:Proteome; D017382:Reactive Oxygen Species; D039221:mRNA Cleavage and Polyadenylation Factors; C086065:PRDX2 protein, human; D054464:Peroxiredoxins; D020796:Receptor, Platelet-Derived Growth Factor alpha