title: Impaired megakaryopoiesis in patients with chronic idiopathic neutropenia is associated with increased transforming growth factor beta1 production in the bone marrow.
abstract: Patients with chronic idiopathic neutropenia (CIN) display relatively low peripheral blood platelet counts and hypo-lobulated megakaryocytes in the bone marrow (BM). The underlying pathogenetic mechanismswere probed by studying the reserves and clonogenic potential of BM megakaryocytic progenitor cells using flow-cytometry and a collagen-based clonogenic assay for the identification of megakaryocyte colony-forming units (CFU-Meg). Thrombopoietin (TPO) and transforming growth factor-beta1 (TGFbeta1) levels were also evaluated in long-term BM culture supernatants using an enzyme-linked immunosorbent assay. CIN patients (n = 39) showed a low proportion of BM CD34(+)/CD61(+) megakaryocytic progenitor cells and low frequency of early and mixed CFU-Meg in the BM mononuclear, but not CD34(+), cell fraction, compared with healthy controls (n = 20). TPO and TGFbeta1 levels were significantly higher in patients compared with controls. TPO levels inversely correlated with platelet counts whereas TGFbeta1 values correlated inversely with CD34(+)/CD61(+) and CFU-Meg megakaryocytic progenitor cell numbers and positively with TPO levels. The addition of an anti-TGFbeta1 neutralising antibody significantly increased the numbers of CFU-Meg in CIN patients but not in controls, compared with baseline. These data suggest that increased local production of TGFbeta1 probably affects the BM megakaryocytic progenitor cell growth in CIN whereas the compensatory production of TPO finally balances the TGFbeta1-induced inhibitory effect.
authors.affiliation: Department of Haematology of the University of Crete School of Medicine, University Hospital of Heraklion, Heraklion, Crete, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Psyllaki
authors.forename: Athina
authors.initials: A
authors.lastname: Damianaki
authors.forename: Claudia
authors.initials: C
authors.lastname: Gemetzi
authors.forename: Katerina
authors.initials: K
authors.lastname: Pyrovolaki
authors.forename: George D
authors.initials: GD
authors.lastname: Eliopoulos
authors.forename: Helen A
authors.initials: HA
authors.lastname: Papadaki
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000276:immunology*; D008875:Middle Aged; D009503:Neutropenia / Q000276:immunology*; D034061:Thrombopoiesis / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*; D053773:Transforming Growth Factor beta1
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1