Endothelial progenitor cells are clonal and exhibit the JAK2V617F 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. (Blood. 2011;117(9):2700-2707)

CD133 marks a stem cell population that drives human primary myelofibrosis

“…In addition, we detected mature cells of several myeloid lineages: erythroblasts, megakaryocytes and monocytes ( Figure 4A,B Figure 4D). Endothelial-like JAK2-V617F + progenitor cells in PMF patients' PB have been reported previously, 27,28 but our study confirms their origin in a CD133 + stem cell. Despite diversity of patients as an independent variable, our CD133…”

Blood and endothelial cells: together through thick and thin

“…Our group recently reported that in some patients with Ph-negative chronic myeloproliferative neoplasms (MPNs), circulating ECFCs exhibit some neoplastic signatures such as JAK2V617F mutation, Suppressor of Cytokine Signaling (SOCS) gene hypermethylation, or clonal derivation. 7 Importantly, these cells had an exaggerated adhesive affinity toward mononuclear cells 7 and shared an increased expression of m-RNA for various adhesive molecules such as ICAM-1, VCAM1, and E-selectin (L.T. and L.M.L., unpublished data, February 8, 2012).…”

Budd-Chiari Syndrome in a Patient with JAK-2 Mutation without Myeloprolifrative Disorder

“…It has been demonstrated that a subset of patients with JAK2V617F MPD have endothelial cells (ECs) that are positive for JAK2V617F and that these cells may possibly contribute to the prothrombotic state [9]. Also this has been demonstrated in some of bone marrow derived of MPD-negative patients and could explain why those patients could develop thrombosis [10].…”