|
|
Blood, 1 May 2005, Vol. 105, No. 9, pp. 3493-3501.
Prepublished online as a Blood First Edition Paper on January 21, 2005; DOI 10.1182/blood-2004-04-1320.
 Previous Article | Table of Contents | Next Article 
HEMATOPOIESIS
A pathobiologic pathway linking thrombopoietin, GATA-1, and TGF- 1 in the development of myelofibrosis
Alessandro M. Vannucchi,
Lucia Bianchi,
Francesco Paoletti,
Alessandro Pancrazzi,
Eugenio Torre,
Mitsuo Nishikawa,
Maria Zingariello,
Angela Di Baldassarre,
Rosa Alba Rana,
Rodolfo Lorenzini,
Elena Alfani,
Giovanni Migliaccio, and
Anna Rita Migliaccio
From the Departments of Hematology and Experimental Pathology and Oncology, University of Florence, Florence Italy; Kirin Brewery Pharmaceutical Research Laboratory, Gunma, Japan; the Department of Biomorphology, University of Chieti, Rome, Italy; and the Quality and Safety of Animal Experimentation and the Departments of Cell Biology and Neurosciences and Hematology, Oncology, and Molecular Medicine, Istituto Superiore Sanità, Rome, Italy.
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  1 (TGF-1) 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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
|
|
