title: A pathobiologic pathway linking thrombopoietin, GATA-1, and TGF-beta1 in the development of myelofibrosis.
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, TPO(high) mice) or intrinsic (hypomorphic GATA-1 mutation, GATA-1(low) 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-1(low) mice contained normal levels of TPO. On the other hand, Mks from TPO-treated wild-type animals (TPO(high) mice), as those from GATA-1(low) animals, had similar morphologic abnormalities and contained low GATA-1. In both animal models, development of myelofibrosis was associated with high transforming growth factor beta1 (TGF-beta1) content in extracellular fluids of marrow and spleen. Surprisingly, TPO treatment of GATA-1(low) mice restored the GATA-1 content in Mks and halted both defective thrombocytopoiesis and fibrosis. These data indicate that the TPO(high) and GATA-1(low) 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.
authors.affiliation: Clinical Biochemistry, Istituto Superiore Sanità, Viale Regina Elena 299, 00161 Rome, Italy. migliar@iss.it
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: Lucia
authors.initials: L
authors.lastname: Bianchi
authors.forename: Francesco
authors.initials: F
authors.lastname: Paoletti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pancrazzi
authors.forename: Eugenio
authors.initials: E
authors.lastname: Torre
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Nishikawa
authors.forename: Maria
authors.initials: M
authors.lastname: Zingariello
authors.forename: Angela
authors.initials: A
authors.lastname: Di Baldassarre
authors.forename: Rosa Alba
authors.initials: RA
authors.lastname: Rana
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Lorenzini
authors.forename: Elena
authors.initials: E
authors.lastname: Alfani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Migliaccio
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Migliaccio
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D008533:Megakaryocytes / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D009154:Mutation; D055728:Primary Myelofibrosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology; D013926:Thrombopoietin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; C508961:Tgfb1 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013926:Thrombopoietin