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Blood, 1 August 2007, Vol. 110, No. 3, pp. 1013-1021. Prepublished online as a Blood First Edition Paper on March 27, 2007; DOI 10.1182/blood-2006-10-054940. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-10-054940v1 110/3/1013    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dupont, S. Articles by Delhommeau, F. Search for Related Content PubMed PubMed Citation Articles by Dupont, S. Articles by Delhommeau, F. Related Collections Hematopoiesis and Stem Cells Oncogenes and Tumor Suppressors Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera Sabrina Dupont1, Aline Massé1, Chloé James1,2, Irène Teyssandier3, Yann Lécluse4, Frédéric Larbret1, Valérie Ugo5, Patrick Saulnier6, Serge Koscielny7, Jean Pierre Le Couédic1, Nicole Casadevall1,3,8, William Vainchenker1, and François Delhommeau1,3,8 1 Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 790, Université Paris Sud, Institut Gustave Roussy, Villejuif; 2 INSERM, E217, Université Victor Ségalen Bordeaux 2, Bordeaux; 3 Assistance Publique–Hopitaux de Paris, Laboratoire d'Hématologie, Hôpital Hôtel–Dieu et Hôpital Saint-Antoine, Paris; 4 Institut Gustave Roussy, Service Commun de Cytométrie, Villejuif; 5 Centre Hospitalier Universitaire de Brest, Laboratoire d'Hématologie, Brest; 6 Institut Gustave Roussy, Laboratoire de Recherche Translationnelle, Villejuif; 7 Institut Gustave Roussy, Department of Biostatistics and Epidemiology, Villejuif; and 8 Université Pierre et Marie Curie, Paris, France The JAK2 617V>F mutation is frequent in polycythemia vera (PV) and essential thrombocythemia (ET). Using quantitative polymerase chain reaction (PCR), we found that high levels of JAK2 617V>F in PV correlate with increased granulocytes and high levels of hemoglobin and endogenous erythroid colony formation. We detected normal progenitors and those that were heterozygous or homozygous for the mutation by genotyping ET and PV clonal immature and committed progenitors. In PV patients, we distinguished homozygous profiles with normal, heterozygous, and homozygous progenitors from heterozygous profiles with only heterozygous and normal progenitors. PV patients with a heterozygous profile had more mutated, committed progenitors than did other PV and ET patients, suggesting a selective amplification of mutated cells in the early phases of hematopoiesis. We demonstrated that mutated erythroid progenitors were more sensitive to erythropoietin than normal progenitors, and that most homozygous erythroid progenitors were erythropoietin independent. Moreover, we observed a greater in vitro erythroid amplification and a selective advantage in vivo for mutated cells in late stages of hematopoiesis. These results suggest that, for PV, erythrocytosis can occur through two mechanisms: terminal erythroid amplification triggered by JAK2 617V>F homozygosity, and a 2-step process including the upstream amplification of heterozygous cells that may involve additional molecular events. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The amount of JAK2 617V>F matters Josef T. Prchal Blood 2007 110: 796-797. [Full Text] [PDF] This article has been cited by other articles: I. Plo, M. Nakatake, L. Malivert, J.-P. de Villartay, S. Giraudier, J.-L. Villeval, L. Wiesmuller, and W. Vainchenker JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders Blood, August 15, 2008; 112(4): 1402 - 1412. [Abstract] [Full Text] [PDF] J. L. Spivak and R. T. Silver The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal Blood, July 15, 2008; 112(2): 231 - 239. [Full Text] [PDF] J.-J. Kiladjian, F. Cervantes, F. W. G. Leebeek, C. Marzac, B. Cassinat, S. Chevret, D. Cazals-Hatem, A. Plessier, J.-C. Garcia-Pagan, S. D. Murad, et al. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases Blood, May 15, 2008; 111(10): 4922 - 4929. [Abstract] [Full Text] [PDF] R. Tiedt, H. Hao-Shen, M. A. Sobas, R. Looser, S. Dirnhofer, J. Schwaller, and R. C. Skoda Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice Blood, April 15, 2008; 111(8): 3931 - 3940. [Abstract] [Full Text] [PDF] S. Li, R. Kralovics, G. De Libero, A. Theocharides, H. Gisslinger, and R. C. Skoda Clonal heterogeneity in polycythemia vera patients with JAK2 exon12 and JAK2-V617F mutations Blood, April 1, 2008; 111(7): 3863 - 3866. [Abstract] [Full Text] [PDF] E. Antonioli, P. Guglielmelli, G. Poli, C. Bogani, A. Pancrazzi, G. Longo, V. Ponziani, L. Tozzi, L. Pieri, V. Santini, et al. Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia Haematologica, January 1, 2008; 93(1): 41 - 48. [Abstract] [Full Text] [PDF] R. Chaligne, C. James, C. Tonetti, R. Besancenot, J. P. Le Couedic, F. Fava, F. Mazurier, I. Godin, K. Maloum, F. Larbret, et al. Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis Blood, November 15, 2007; 110(10): 3735 - 3743. [Abstract] [Full Text] [PDF]

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