Cho S.Y.,Mount Sinai School of Medicine |
Xu M.,Mount Sinai School of Medicine |
Xu M.,Myeloproliferative Disorder Research Consortium |
Roboz J.,Mount Sinai School of Medicine |
And 4 more authors.
Cancer Research | Year: 2010
Primary myelofibrosis (PMF) and polycythemia vera (PV) are chronic myeloproliferative neoplasms. PMF and, to a lesser degree, PV are characterized by constitutive mobilization of hematopoietic stem cells (HSC) and progenitor cells (HPC) into the peripheral blood (PB). The interaction between the chemokine CXCL12 and its receptor CXCR4 plays a pivotal role in determining the trafficking of CD34+ cells between the bone marrow (BM) and the PB. PMF, but not PV, is associated with downregulation of CXCR4 by CD34+ cells due to epigenetic events. Both PV and PMF patients have elevated levels of immunoreactive forms of CXCL12 in the BM and PB. Using electrospray mass spectrometry, the PB and BM plasma of PV and PMF patients was shown to contain reduced amounts of intact CXCL12 but significant amounts of several truncated forms of CXCL12, which are lacking in normal PB and BM plasma. These truncated forms of CXCL12 are the product of the action of several serine proteases, including dipeptidyl peptidase-IV, neutrophil elastase, matrix metalloproteinase-2 (MMP-2), MMP-9, and cathepsin G. Unlike CXCL12, these truncates either lack the ability to act as a chemoattractant for CD34 + cells and/or act as an antagonist to the action of CXCL12. These data suggest that proteolytic degradation of CXCL12 is characteristic of both PV and PMF and that the resulting truncated forms of CXCL12, in addition to the reduced expression of CXCR4 by CD34+ cells, lead to a profound mobilization of HSC/HPC in PMF. ©2010 AACR.
Sozer S.,Istanbul University |
Sozer S.,Mount Sinai School of Medicine |
Hoffman R.,Mount Sinai School of Medicine |
Hoffman R.,Myeloproliferative Disorder Research Consortium
Methods in Molecular Biology | Year: 2011
Myeloproliferative neoplasms (MPN) are clonal hematological malignancies that are frequently-associated with an acquired somatic mutation in JAK2 (JAK2V617F). Patients with MPN are at a high risk of developing thrombotic events. Endothelial cell (EC) abnormalities are thought to contribute to this prothrombotic state. Budd-Chiari syndrome (BCS) and portal vein thromboses have been reported to be associated with JAK2V617F positive hematopoiesis. We explored whether JAK2V617F was present in ECs within the vessels of polycythemia vera (PV) patients with BCS using laser-capture microdissection followed by nested PCR or real-time RT-PCR. The presence of JAK2V617F in both ECs and hematopoietic cells belonging to BCS patients with PV indicates that ECs from these patients are involved by the malignant process and that in this subpopulation of patients the disease may originate from a cell common to hematopoietic and endothelial cells. © 2011 Springer Science+Business Media, LLC.
Lu M.,Mount Sinai School of Medicine |
Zhang W.,Mount Sinai School of Medicine |
Li Y.,Mount Sinai School of Medicine |
Berenzon D.,Mount Sinai School of Medicine |
And 8 more authors.
Experimental Hematology | Year: 2010
Objective: Interferon-α (IFNα) therapy leads to hematological remissions and a reduction of the JAK2V617F allele burden in patients with polycythemia vera (PV). In this study, the cellular target by which IFNα affects hematopoiesis in PV patients was evaluated. Materials and Methods: CD34+ cells were isolated from normal bone marrow and the peripheral blood of patients with PV and were treated in vitro with each of the three commercially available forms of IFNα: IFNα 2b, pegylated IFNα 2a (Peg-IFNα 2a), and pegylated IFNα 2b (Peg-IFNα 2b). Results: Each form of IFNα was equally potent in suppressing hematopoietic colony formation by normal CD34+ cells, but Peg-IFNα 2a and IFNα 2b were more effective than Peg-IFNα 2b in inhibiting burst-forming unit erythroid-derived colony formation by PV CD34+ cells. In addition, exposure of PV CD34+ cells to equal doses of Peg-IFNα 2a and IFNα 2b resulted in a 38% to 40% reduction in the proportion of JAK2V617F-positive hematopoietic progenitor cells (HPC), while equivalent doses of Peg-IFNα 2b did not reduce the number of malignant HPC. Further studies explored the mechanism by which IFNα induced PV HPC growth inhibition. Treatment of Peg-IFNα 2a increased the rate of apoptosis of PV CD34+ cells and the phosphorylation/activation of p38 mitogen-activated protein kinase in PV CD34+ cells, while the p38-specific inhibitor SB203580 reversed the growth inhibition and apoptosis induced by Peg-IFNα 2a. Conclusion: These data suggest that low doses of IFNα selectively and directly suppress PV JAK2V617F HPC and that these agents act through the p38 mitogen-activated protein kinase pathway. © 2010 ISEH - Society for Hematology and Stem Cells.