Proteasome inhibitor bortezomib impairs both myelofibrosis and osteosclerosis induced by high thrombopoietin levels in mice.
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-kappaB 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 TPO(high) 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-kappaB activation in vitro in murine megakaryocytes. It also inhibited NF-kappaB activation in vivo in TPO(high) mice leading to decreased IL-1alpha plasma levels. After 4 weeks of treatment, bortezomib decreased TGF-beta1 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 TPO(high) mouse survival (89% vs 8% at week 52). We conclude that bortezomib appears as a promising therapy for future treatment of PMF patients.
Wagner-Ballon
Orianne
O
Institut National de la Santé et de la Recherche Médicale, U790, Université Paris XI, Villejuif, France.
Pisani
Didier F
DF
Gastinne
Thomas
T
Tulliez
Micheline
M
Chaligné
Ronan
R
Lacout
Catherine
C
Auradé
Frédéric
F
Villeval
Jean-Luc
JL
Gonin
Patrick
P
Vainchenker
William
W
Giraudier
Stéphane
S
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D004195:Disease Models, Animal; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010026:Osteosclerosis / Q000139:chemically induced / Q000188:drug therapy*; D055728:Primary Myelofibrosis / Q000139:chemically induced / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D015996:Survival Rate; D013926:Thrombopoietin / Q000009:adverse effects* / Q000097:blood
D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D013926:Thrombopoietin