title: Differential expression of SDF-1 receptor CXCR4 in molecularly defined forms of inherited thrombocytopenias.
abstract: The SDF-1-CXCR4 axis plays an essential role in the regulation of platelet production, by directing megakaryocyte (MK) migration toward the vascular niche, thus allowing terminal maturation and proplatelet formation, and also regulates platelet function in an autocrine manner. Inherited thrombocytopenias (IT) comprise a spectrum of diverse clinical conditions caused by mutations in genes involved in platelet production and function. We assessed CXCR4 expression and SDF-1 levels in a panel of well-characterized forms of IT. Decreased surface CXCR4 levels were found in 8 of 27 (29.6%) IT patients by flow cytometry, including 4 of 6 patients with ANKRD26-RT, 3 of 3 patients with GPS and 1 of 6 patients with FPD/AML. Low CXCR4 levels were associated with impaired SDF-1-triggered platelet aggregation, indicating that this decrease is functionally relevant, whereas a normal platelet response was shown in patients harbouring preserved membrane CXCR4. Reduced CXCR4 was not due to decreased gene expression, as platelet RNA levels were normal or increased, suggesting a post-transcriptional defect. Increased ligand-induced receptor internalization was ruled out, as circulating SDF-1 levels were similar to controls. MK CXCR4 expression was normal, indicating that the defect in CXCR4 arises after the step of platelet biogenesis. In conclusion, the finding of defective CXCR4 expression specifically associated with certain IT disorders highlights the fact that abnormalities in several megakaryocytic regulators underlie IT pathogenesis and further reveal the heterogeneous nature of these conditions.
authors.affiliation: a Hematology Research, Institute for Medical Research (IDIM) A. Lanari, University of Buenos Aires (UBA) , National Council for Medical Research (CONICET) , Buenos Aires , Argentina.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Salim
authors.affiliation: a Hematology Research, Institute for Medical Research (IDIM) A. Lanari, University of Buenos Aires (UBA) , National Council for Medical Research (CONICET) , Buenos Aires , Argentina.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Glembotsky
authors.affiliation: a Hematology Research, Institute for Medical Research (IDIM) A. Lanari, University of Buenos Aires (UBA) , National Council for Medical Research (CONICET) , Buenos Aires , Argentina.
authors.forename: Paola R
authors.initials: PR
authors.lastname: Lev
authors.affiliation: a Hematology Research, Institute for Medical Research (IDIM) A. Lanari, University of Buenos Aires (UBA) , National Council for Medical Research (CONICET) , Buenos Aires , Argentina.
authors.forename: Cecilia P
authors.initials: CP
authors.lastname: Marin Oyarzún
authors.affiliation: a Hematology Research, Institute for Medical Research (IDIM) A. Lanari, University of Buenos Aires (UBA) , National Council for Medical Research (CONICET) , Buenos Aires , Argentina.
authors.forename: Nora P
authors.initials: NP
authors.lastname: Goette
authors.affiliation: a Hematology Research, Institute for Medical Research (IDIM) A. Lanari, University of Buenos Aires (UBA) , National Council for Medical Research (CONICET) , Buenos Aires , Argentina.
authors.forename: Felisa C
authors.initials: FC
authors.lastname: Molinas
authors.affiliation: a Hematology Research, Institute for Medical Research (IDIM) A. Lanari, University of Buenos Aires (UBA) , National Council for Medical Research (CONICET) , Buenos Aires , Argentina.
authors.forename: Rosana F
authors.initials: RF
authors.lastname: Marta
authors.affiliation: a Hematology Research, Institute for Medical Research (IDIM) A. Lanari, University of Buenos Aires (UBA) , National Council for Medical Research (CONICET) , Buenos Aires , Argentina.
authors.forename: Paula G
authors.initials: PG
authors.lastname: Heller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D054377:Chemokine CXCL12 / Q000096:biosynthesis*; D002648:Child; D005260:Female; D005786:Gene Expression Regulation; D030342:Genetic Diseases, Inborn / Q000097:blood* / Q000235:genetics / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010974:Platelet Aggregation / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D013921:Thrombocytopenia / Q000097:blood* / Q000235:genetics / Q000473:pathology
chemical_list: C583630:ANKRD26 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D019718:Receptors, CXCR4
keywords: CXCR4; SDF-1; inherited thrombocytopenias