title: Endothelial progenitor cells are clonal and exhibit the JAK2(V617F) mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms.
abstract: In this study we investigated whether neoplastic transformation occurring in Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs) could involve also the endothelial cell compartment. We evaluated the level of endothelial colony-forming cells (E-CFCs) in 42 patients (15 with polycythemia vera, 12 with essential thrombocythemia, and 15 with primary myelofibrosis). All patients had 1 molecular abnormality (JAK2(V617F) or MPL(W515K) mutations, SOCS gene hypermethylation, clonal pattern of growth) detectable in their granulocytes. The growth of colonies was obtained in 22 patients and, among them, patients with primary myelofibrosis exhibited the highest level of E-CFCs. We found that E-CFCs exhibited no molecular abnormalities in12 patients, had SOCS gene hypermethylation, were polyclonal at human androgen receptor analysis in 5 patients, and resulted in JAK2(V617F) mutated and clonal in 5 additional patients, all experiencing thrombotic complications. On the whole, patients with altered E-CFCs required antiproliferative therapy more frequently than patients with normal E-CFCs. Moreover JAK2(V617F)-positive E-CFCs showed signal transducer and activator of transcription 5 and 3 phosphorylation rates higher than E-CFCs isolated from healthy persons and patients with MPN without molecular abnormalities. Finally, JAK2(V617F)-positive E-CFCs exhibited a high proficiency to adhere to normal mononuclear cells. This study highlights a novel mechanism underlying the thrombophilia observed in MPN.
authors.affiliation: Department of Hematology, Catholic University, Rome, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Teofili
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martini
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Iachininoto
authors.forename: Sara
authors.initials: S
authors.lastname: Capodimonti
authors.forename: Eugenia Rosa
authors.initials: ER
authors.lastname: Nuzzolo
authors.forename: Lorenza
authors.initials: L
authors.lastname: Torti
authors.forename: Tonia
authors.initials: T
authors.lastname: Cenci
authors.forename: Luigi Maria
authors.initials: LM
authors.lastname: Larocca
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Leone
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D002448:Cell Adhesion; D049109:Cell Proliferation; D002469:Cell Separation; D002999:Clone Cells; D003114:Colony-Forming Units Assay; D042783:Endothelial Cells / Q000473:pathology*; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000150:complications / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D010677:Philadelphia Chromosome; D010766:Phosphorylation; D050791:STAT Transcription Factors / Q000378:metabolism; D013234:Stem Cells / Q000201:enzymology* / Q000473:pathology; D013388:Succinimides / Q000378:metabolism; D013927:Thrombosis / Q000150:complications* / Q000473:pathology
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D015415:Biomarkers; D005452:Fluoresceins; D050791:STAT Transcription Factors; D013388:Succinimides; D053614:Janus Kinase 2