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Blood, 1 July 2007, Vol. 110, No. 1, pp. 345-353. Prepublished online as a Blood First Edition Paper on March 20, 2007; DOI 10.1182/blood-2006-10-054502. This Article Full Text (PDF) All Versions of this Article: blood-2006-10-054502v1 110/1/345    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 Wagner-Ballon, O. Articles by Giraudier, S. Search for Related Content PubMed PubMed Citation Articles by Wagner-Ballon, O. Articles by Giraudier, S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 26, 2006 Accepted March 16, 2007 Proteasome inhibitor bortezomib impairs both myelofibrosis and osteosclerosis induced by high thrombopoietin levels in mice Orianne Wagner-Ballon, Didier F Pisani, Thomas Gastinne, Micheline Tulliez, Ronan Chaligne, Catherine Lacout, Frederic Aurade, Jean-Luc Villeval, Patrick Gonin, William Vainchenker, and Stephane Giraudier* INSERM, U790, Universite Paris XI, Villejuif, France Institut Gustave Roussy, Villejuif, France AP-HP, Laboratoire d'Anatomo-pathologie, Hopital Cochin, Paris, France Universite Paris XI, IFR54, Service Commun d'Experimentation Animale, Institute Gustave Roussy, Villejuif, France AP-HP Laboratoire d'Hematologie, Hopital Henri Mondor, Creteil, France * Corresponding author; email: stephane.giraudier{at}hmn.aphp.fr. Myelofibrosis with myeloid metaplasia (MMM) is the most serious myeloproliferative disorder, characterized by clonal myeloproliferation associated with cytokine-mediated bone marrow stromal reaction including fibrosis and osteosclerosis. Current drug therapy remains mainly palliative. Since the NF-B pathway is implicated in the abnormal release of cytokines in MMM, the proteasome inhibitor bortezomib might be a potential therapy. In order to test its effect, we used the lethal murine model of myelofibrosis induced by thrombopoietin (TPO) overexpression. In this TPOhigh model, the development of the disease is related to a deregulated MPL signaling, as recently described in MMM patients. We first demonstrated that bortezomib was able to inhibit TPO-induced NF-B activation in vitro in murine megakaryocytes. It also inhibited NF-B activation in vivo in TPOhigh mice leading to decreased IL-1 plasma levels. After 4 weeks of treatment, bortezomib decreased TGF-1 levels in marrow fluids and impaired marrow and spleen fibrosis development. After 12 weeks of treatment, bortezomib also impaired osteosclerosis development, through osteoprotegerin inhibition. Moreover, this drug reduced myeloproliferation induced by high TPO level. Finally, bortezomib dramatically improved TPOhigh mice survival (89% vs 8% at week 52). We conclude that bortezomib appears as a promising therapy for future treatment of MMM patients. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Myelofibrosis with myeloid metaplasia: targeted therapy Mitchell S. Cairo Blood 2007 110: 2-3. [Full Text] [PDF] This article has been cited by other articles: Z. Jagani, K. Song, J. L. Kutok, M. R. Dewar, A. Melet, T. Santos, A. Grassian, S. Ghaffari, C. Wu, R. Ren, et al. Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL-Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors Cancer Res., August 15, 2009; 69(16): 6546 - 6555. [Abstract] [Full Text] [PDF] E. Kastritis, M. Migkou, M. Gavriatopoulou, P. Zirogiannis, V. Hadjikonstantinou, and M. A. Dimopoulos Treatment of light chain deposition disease with bortezomib and dexamethasone Haematologica, February 1, 2009; 94(2): 300 - 302. [Full Text] [PDF] J.-J. Lataillade, O. Pierre-Louis, H. C. Hasselbalch, G. Uzan, C. Jasmin, M.-C. Martyre, M.-C. Le Bousse-Kerdiles, and on behalf of the French INSERM and the European EU Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence Blood, October 15, 2008; 112(8): 3026 - 3035. [Abstract] [Full Text] [PDF] S. Fineschi, M. Bongiovanni, Y. Donati, S. Djaafar, F. Naso, L. Goffin, C. Barazzone Argiroffo, J.-C. Pache, J.-M. Dayer, S. Ferrari-Lacraz, et al. In Vivo Investigations on Anti-Fibrotic Potential of Proteasome Inhibition in Lung and Skin Fibrosis Am. J. Respir. Cell Mol. Biol., October 1, 2008; 39(4): 458 - 465. [Abstract] [Full Text] [PDF] A. Rambaldi, T. Barbui, and G. Barosi From Palliation to Epigenetic Therapy in Myelofibrosis Hematology, January 1, 2008; 2008(1): 83 - 91. [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] R. Hoffman and D. Rondelli Biology and Treatment of Primary Myelofibrosis Hematology, January 1, 2007; 2007(1): 346 - 354. [Abstract] [Full Text] [PDF]

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