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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.
NEOPLASIA Proteasome inhibitor bortezomib impairs both myelofibrosis and osteosclerosis induced by high thrombopoietin levels in mice1 Institut National de la Santé et de la Recherche Médicale (INSERM), U790, Université Paris XI, Villejuif, France; 2 Institut Gustave Roussy, Villejuif, France; 3 Assistance Publique des Hôpitaux de Paris (AP-HP), Laboratoire d'Hématologie, Hôpital Henri Mondor, Université Paris XII, Créteil, France; 4 AP-HP, Laboratoire d'Anatomo-pathologie, Hôpital Cochin, Paris, France; 5 Université Paris XI, IFR54, Service Commun d'Expérimentation Animale, Institut Gustave Roussy, Villejuif, France
Primary myelofibrosis (PMF) 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. Because the NF-
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
B pathway is implicated in the abnormal release of cytokines in PMF, the proteasome inhibitor bortezomib might be a potential therapy. 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 PMF patients. We first demonstrated that bortezomib was able to inhibit TPO-induced NF-
plasma levels. After 4 weeks of treatment, bortezomib decreased TGF-ß1 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 mouse survival (89% vs 8% at week 52). We conclude that bortezomib appears as a promising therapy for future treatment of PMF patients. 
