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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-04-1133.
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Blood, 15 November 2002, Vol. 100, No. 10, pp. 3495-3503
HEMATOPOIESIS
Prominent role of TGF- 1 in
thrombopoietin-induced myelofibrosis in mice
Hédia Chagraoui,
Emiko Komura,
Micheline Tulliez,
Stéphane Giraudier,
William Vainchenker, and
Françoise Wendling
From INSERM U362, Institut Gustave Roussy, Villejuif,
France; and Hôpital Cochin, Laboratoire
d'Anatomopathologie, Paris, France.
Several studies suggest an implication of transforming growth
factor- 1 (TGF-1) 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-1 in
the pathogenesis of myelofibrosis, bone marrow stem cells from homozygous TGF-1 null (TGF-1 /) 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-1/ cells (chimerism > 70%) showed deposition
of reticulin fibers at any time during the follow-up. In accordance
with the development of fibrosis, latent TGF-1 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-1/ cells. These data provide evidence that
TGF-1 produced by hematopoietic cells is pivotal for the
pathogenesis of myelofibrosis that develops in mice with TPO overexpression.
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