Prominent role of TGF-β1 in thrombopoietin-induced myelofibrosis in mice

H Chagraoui, E Komura, M Tulliez… - Blood, The Journal …, 2002 - ashpublications.org
H Chagraoui, E Komura, M Tulliez, S Giraudier, W Vainchenker, F Wendling
Blood, The Journal of the American Society of Hematology, 2002ashpublications.org
Several studies suggest an implication of transforming growth factor-β1 (TGF-β1) in the
promotion of myelofibrosis associated with hematopoietic malignancies, but the involvement
of this cytokine is not fully investigated. To test directly the impact of TGF-β1 in the
pathogenesis of myelofibrosis, bone marrow stem cells from homozygous TGF-β1 null (TGF-
β1−/−) and wild-type (WT) littermates were infected with a retrovirus encoding the murine
thrombopoietin (TPO) protein and engrafted into lethally irradiated wild-type hosts for long …
Several studies suggest an implication of transforming growth factor-β1 (TGF-β1) in the promotion of myelofibrosis associated with hematopoietic malignancies, but the involvement of this cytokine is not fully investigated. To test directly the impact of TGF-β1 in the pathogenesis of myelofibrosis, bone marrow stem cells from homozygous TGF-β1 null (TGF-β1−/−) and wild-type (WT) littermates were infected with a retrovirus encoding the murine thrombopoietin (TPO) protein and engrafted into lethally irradiated wild-type hosts for long-term reconstitution. Over the 4 months of follow-up, TPO levels in plasma were markedly elevated in both groups of mice, and animals typically developed a myeloproliferative syndrome characterized by thrombocytosis, leukocytosis, splenomegaly, increased numbers of progenitors in blood, and extramedullary hematopoiesis. Severe fibrosis was observed in spleen and marrow from all the mice engrafted with WT cells. In contrast, none of the mice repopulated with TGF-β1−/− cells (chimerism > 70%) showed deposition of reticulin fibers at any time during the follow-up. In accordance with the development of fibrosis, latent TGF-β1 levels in plasma and extracellular fluid of the spleen from mice engrafted with WT cells were increased 6-fold and 4-fold, respectively, over levels found in normal hosts, whereas no increase over baseline levels could be demonstrated in animals undergoing transplantation with TGF-β1−/− cells. These data provide evidence that TGF-β1 produced by hematopoietic cells is pivotal for the pathogenesis of myelofibrosis that develops in mice with TPO overexpression.
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