title: Platelet proteome analysis reveals integrin-dependent aggregation defects in patients with myelodysplastic syndromes.
abstract: Bleeding complications are a significant clinical problem in patients with myelodysplastic syndromes even at sufficient platelet counts (>50,000/μl). However, the underlying pathology of this hemorrhagic diathesis is still unknown. Here, we analyzed the platelet proteome of patients with myelodysplastic syndromes by quantitative two-dimensional difference gel electrophoresis followed by mass spectrometric protein identification. Proteins identified with lower concentrations, such as Talin-1, Vinculin, Myosin-9, Filmain-A, and Actin play critical roles in integrin αIIbβ3 signaling and thus platelet aggregation. Despite normal agonist receptor expression, calcium flux, and granule release upon activation, the activation capacity of integrin αIIbβ3 was diminished in myelodysplastic syndrome platelets. Förster resonance energy transfer analysis showed a reduced co-localization of Talin-1 to the integrin's β3-subunit, which is required for receptor activation and fibrinogen binding. In addition, platelet spreading on immobilized fibrinogen was incomplete, and platelet aggregation assays confirmed a general defect in integrin-dependent platelet aggregation in patients with myelodysplastic syndromes. Our data provide novel aspects on the molecular pathology of impaired platelet function in myelodysplastic syndromes and suggest a mechanism of defective integrin αIIbβ3 signaling that may contribute to the hemorrhagic diathesis observed in these patients.
authors: Department of Hematology, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors: Julia
authors: J
authors: Fröbel
authors: Ron-Patrick
authors: RP
authors: Cadeddu
authors: Sonja
authors: S
authors: Hartwig
authors: Ingmar
authors: I
authors: Bruns
authors: Christian M
authors: CM
authors: Wilk
authors: Andrea
authors: A
authors: Kündgen
authors: Johannes C
authors: JC
authors: Fischer
authors: Thomas
authors: T
authors: Schroeder
authors: Ulrich G
authors: UG
authors: Steidl
authors: Ulrich
authors: U
authors: Germing
authors: Stefan
authors: S
authors: Lehr
authors: Rainer
authors: R
authors: Haas
authors: Akos
authors: A
authors: Czibere
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016718:Arachidonic Acid / Q000502:physiology; D001792:Blood Platelets / Q000378:metabolism*; D002448:Cell Adhesion; D002478:Cells, Cultured; D003094:Collagen / Q000502:physiology; D005260:Female; D006801:Humans; D016023:Integrins / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000378:metabolism / Q000503:physiopathology*; D010974:Platelet Aggregation; D060066:Protein Interaction Maps; D020543:Proteome / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D016023:Integrins; D020543:Proteome; D011956:Receptors, Cell Surface; D016718:Arachidonic Acid; D003094:Collagen
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