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Blood, 1 May 2006, Vol. 107, No. 9, pp. 3495-3502. Prepublished online as a Blood First Edition Paper on December 29, 2005; DOI 10.1182/blood-2005-07-3037. This Article Full Text (PDF) All Versions of this Article: 2005-07-3037v1 107/9/3495    most recent Alert me when this article is cited Alert me if a correction is posted 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 Zeuner, A. Articles by De Maria, R. Search for Related Content PubMed PubMed Citation Articles by Zeuner, A. Articles by De Maria, R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 28, 2005 Accepted December 16, 2005 Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells Ann Zeuner*, Francesca Pedini, Michele Signore, Giusy Ruscio, Carlo Messina, Agostino Tafuri, Gabriella Girelli, Cesare Peschle, and Ruggero De Maria Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy; Department of Experimental Oncology, Istituto Oncologico del Mediterraneo, Catania, Italy Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy Department of Hematology and Cellular Biotechnology, University La Sapienza, Rome, Italy Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA * Corresponding author; email: a.zeuner{at}iss.it. Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by an excessive erythrocyte production. The majority of PV patients harbor an activating JAK2 mutation, but the molecular links between this mutation and erythrocyte overproduction are unknown. The interaction between death receptors and their ligands contributes to the physiological regulation of erythropoiesis through the inhibition of erythroblast proliferation and differentiation. Using an in vitro culture system to generate differentiating erythroid cells, we found that erythroblasts derived from PV patients harboring the JAK2 V617F mutation were able to proliferate and generate higher numbers of mature erythroid cells in the presence of inhibitory signals delivered by CD95 (Fas/Apo-1) and TRAIL receptor stimulation. JAK2-mutated PV erythroblasts showed lower levels of CD95-induced caspase activation and incomplete caspase-mediated cleavage of the erythroid transcription factor GATA-1, which was entirely degraded in normal erythroblasts upon CD95 stimulation. JAK2 mutation was associated in PV erythroblasts with cytokine-independent activation of the JAK2 effectors Akt/PKB and ERK/MAP and with a deregulated expression of c-FLIPshort, a potent cellular inhibitor of death receptor-induced apoptosis. These results show the presence in PV erythroblasts of proliferative and antiapoptotic signals that may link the JAK2 V617F mutation with inhibition of death receptor signalling, possibly contributing to a deregulation of erythropoiesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Polycythemia vera erythroblasts: too tough to die Henning Walczak Blood 2006 107: 3422-3423. [Full Text] [PDF] This article has been cited by other articles: A. Zeuner, F. Pedini, F. Francescangeli, M. Signore, G. Girelli, A. Tafuri, and R. De Maria Activity of the BH3 mimetic ABT-737 on polycythemia vera erythroid precursor cells Blood, February 12, 2009; 113(7): 1522 - 1525. [Abstract] [Full Text] [PDF] P. Sathyanarayana, A. Dev, J. Fang, E. Houde, O. Bogacheva, O. Bogachev, M. Menon, S. Browne, A. Pradeep, C. Emerson, et al. EPO receptor circuits for primary erythroblast survival Blood, June 1, 2008; 111(11): 5390 - 5399. [Abstract] [Full Text] [PDF] A. Zeuner, M. Signore, D. Martinetti, M. Bartucci, C. Peschle, and R. De Maria Chemotherapy-Induced Thrombocytopenia Derives from the Selective Death of Megakaryocyte Progenitors and Can Be Rescued by Stem Cell Factor Cancer Res., May 15, 2007; 67(10): 4767 - 4773. [Abstract] [Full Text] [PDF] P. J. Campbell and A. R. Green The Myeloproliferative Disorders N. Engl. J. Med., December 7, 2006; 355(23): 2452 - 2466. [Full Text] [PDF] T. G.P. Bumm, C. Elsea, A. S. Corbin, M. Loriaux, D. Sherbenou, L. Wood, J. Deininger, R. T. Silver, B. J. Druker, and M. W.N. Deininger Characterization of Murine JAK2V617F-Positive Myeloproliferative Disease Cancer Res., December 1, 2006; 66(23): 11156 - 11165. [Abstract] [Full Text] [PDF]

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