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Monocyte/Macrophage Dysfunctions Do Not Impair the Promotion of Myelofibrosis by High Levels of Thrombopoietin¹

Orianne Wagner-Ballon^*,, Hédia Chagraoui^2,*, Eric Prina^2,, Micheline Tulliez, Geneviève Milon, Hana Raslova^*, Jean-Luc Villeval^*, William Vainchenker^* and Stéphane Giraudier^3,*,

^* Institut National de la Sante et de la Recherche Medicale (INSERM) U790, Pavillon de Recherche 1, Institut Gustave Roussy, Villejuif, France; Laboratoire d’Hématologie, Hôpital Henri Mondor, Créteil, France; Unité Immunophysiologie et Parasitisme Intracellulaire, Institut Pasteur, Paris, France; and Laboratoire d’Anatomopathologie, Hôpital Cochin, Paris, France

Several lines of evidence indicate that the megakaryocyte/platelet lineage is crucial in myelofibrosis induction. The demonstration that NOD/SCID mice with functionally deficient monocytes do not develop fibrotic changes when exposed to thrombopoietin (TPO) also suggests an important role for monocyte/macrophages. However, in this animal model, the development of myelofibrosis is dependent on the level of TPO. This study was conducted to investigate whether NOD/SCID mice exposed to high TPO levels mediated by a retroviral vector would be refractory to the development of bone marrow fibrosis. We show that TPO and TGF-1 in plasma from NOD/SCID and SCID mice engrafted with TPO-overexpressing hemopoietic cells reach levels similar to the ones reached in immunocompetent mice, and all animals develop a myeloproliferative disease associated with a dense myelofibrosis at 8 wk posttransplantation. Monocytes in NOD/SCID mice are functionally deficient to secrete cytokines such as IL-1 in response to stimuli, even under TPO expression. Surprisingly, the plasma of these mice displays high levels of IL-, which was demonstrated to originate from platelets. Together, these data suggest that completely functional monocytes are not required to develop myelofibrosis and that platelets are able, under TPO stimulation, to synthesize inflammatory cytokines, which may be involved in the pathogenesis of myelofibrosis and osteosclerosis.

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