A pathobiologic pathway linking thrombopoietin, GATA-1, and TGF-β1 in the development of myelofibrosis

AM Vannucchi, L Bianchi, F Paoletti, A Pancrazzi… - Blood, 2005 - ashpublications.org
AM Vannucchi, L Bianchi, F Paoletti, A Pancrazzi, E Torre, M Nishikawa, M Zingariello
Blood, 2005ashpublications.org
Idiopathic myelofibrosis (IM) is a disease characterized by marrow fibrosis, abnormal
stem/progenitor cell trafficking, and extramedullary hematopoiesis frequently associated with
alterations in megakaryocytes (Mks). Mice harboring genetic alterations in either the
extrinsic (ectopic thrombopoietin expression, TPOhigh mice) or intrinsic (hypomorphic GATA-
1 mutation, GATA-1low mice) control of Mk differentiation develop myelofibrosis, a syndrome
similar to IM. The relationship, if any, between the pathobiologic mechanism leading to the …
Abstract
Idiopathic myelofibrosis (IM) is a disease characterized by marrow fibrosis, abnormal stem/progenitor cell trafficking, and extramedullary hematopoiesis frequently associated with alterations in megakaryocytes (Mks). Mice harboring genetic alterations in either the extrinsic (ectopic thrombopoietin expression, TPOhigh mice) or intrinsic (hypomorphic GATA-1 mutation, GATA-1low mice) control of Mk differentiation develop myelofibrosis, a syndrome similar to IM. The relationship, if any, between the pathobiologic mechanism leading to the development of myelofibrosis in the 2 animal models is not understood. Here we show that plasma from GATA-1low mice contained normal levels of TPO. On the other hand, Mks from TPO-treated wild-type animals (TPOhigh mice), as those from GATA-1low animals, had similar morphologic abnormalities and contained low GATA-1. In both animal models, development of myelofibrosis was associated with high transforming growth factor β1 (TGF-β1) content in extracellular fluids of marrow and spleen. Surprisingly, TPO treatment of GATA-1low mice restored the GATA-1 content in Mks and halted both defective thrombocytopoiesis and fibrosis. These data indicate that the TPOhigh and GATA-1low alterations are linked in an upstream-downstream relationship along a pathobiologic pathway leading to development of myelofibrosis in mice and, possibly, of IM in humans.
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