title: Accelerated telomere shortening in glycosylphosphatidylinositol (GPI)-negative compared with GPI-positive granulocytes from patients with paroxysmal nocturnal hemoglobinuria (PNH) detected by proaerolysin flow-FISH.
abstract: Telomere length has been linked to disease stage and degree of (pan-)cytopenia in patients with bone marrow failure syndromes. The aim of the current study was to analyze the impact of replicative stress on telomere length in residual glycosylphosphatidylinositol-positive (GPI+) versus GPI- hematopoiesis in patients with paroxysmal nocturnal hemoglobinuria (PNH). Peripheral blood granulocytes from 16 patients and 22 healthy individuals were analyzed. For this purpose, we developed proaerolysin flow-FISH, a novel methodology that combines proaerolysin staining (for GPI expression) with flow-FISH (for telomere length measurement). We found significantly shortened telomeres in GPI- granulocytes (mean +/- SE: 6.26 +/- 0.27 telomere fluorescence units [TFU]), both compared with their GPI+ counterparts (6.88 +/- 0.38 TFU; P = .03) as well as with age-matched healthy individuals (7.73 +/- 0.23 TFU; P < .001). Our findings are in support of a selective growth advantage model of PNH assuming that damage to the GPI+ hematopoietic stem-cell (HSC) compartment leads to compensatory hyperproliferation of residual GPI- HSCs.
authors.affiliation: Division of Hematology, Oncology and Immunology, Department of Medical Biometry, University of Tübingen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Beier
authors.forename: Stefan
authors.initials: S
authors.lastname: Balabanov
authors.forename: Tom
authors.initials: T
authors.lastname: Buckley
authors.forename: Klaus
authors.initials: K
authors.lastname: Dietz
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hartmann
authors.forename: Markus
authors.initials: M
authors.lastname: Rojewski
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.forename: Hubert
authors.initials: H
authors.lastname: Schrezenmeier
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001427:Bacterial Toxins; D016022:Case-Control Studies; D017261:Glycosylphosphatidylinositols / Q000097:blood*; D006098:Granulocytes / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood* / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008875:Middle Aged; D052899:Pore Forming Cytotoxic Proteins; D016615:Telomere / Q000235:genetics* / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D017261:Glycosylphosphatidylinositols; D052899:Pore Forming Cytotoxic Proteins; C107096:proaerolysin