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A model of myelofibrosis and osteosclerosis in mice induced by
overexpressing thrombopoietin (mpl ligand): reversal of disease by bone
marrow transplantation
XQ Yan, D Lacey, D Hill, Y Chen, F Fletcher, RG Hawley and IK McNiece
Department of Developmental Hematology, Amgen Inc, Thousand Oaks, CA
91320-1789, USA.
We have previously shown that mice induced to overexpress thrombopoietin
(TPO) by retroviral-mediated gene transfer into bone marrow (BM) cells
develop myelofibrosis and osteosclerosis. It was speculated that these
effects were secondary to TPO, resulting from high levels of megakaryocytes
and platelets. Also, it was proposed that these mice represent a model for
myelofibrosis and osteosclerosis. In this report, we show that levels of
both transforming growth factor- beta 1 and platelet-derived growth factor
are increased twofold to fivefold in the platelet-poor plasma of TPO
overexpressing mice compared with control mice. These data suggest that the
increased megakaryocytes produce elevated levels of these cytokines that
lead to the pathogenesis of disease. Further, we retransplanted TPO
overexpressing mice, at 40 to 42 weeks after primary transplantation, with
normal BM cells. After the secondary transplantation, megakaryocytes and
platelets returned to normal levels and the myelofibrosis and
osteosclerosis were completely corrected. These data extend our initial
studies of the effects of overexpression of TPO and show the potential use
of this model to explore the underlying cause of myelofibrosis and
osteosclerosis and potential treatments for these diseases.
Volume 88,
Issue 2,
pp. 402-409,
07/15/1996
Copyright © 1996 by The American Society of Hematology
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