title: Activation of non-canonical TGF-β1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis.
abstract: Primary myelofibrosis (PMF) is characterized by megakaryocyte hyperplasia, dysplasia and death with progressive reticulin/collagen fibrosis in marrow and hematopoiesis in extramedullary sites. The mechanism of fibrosis was investigated by comparing TGF-β1 signaling of marrow and spleen of patients with PMF and of non-diseased individuals. Expression of 39 (23 up-regulated and 16 down-regulated) and 38 (8 up-regulated and 30 down-regulated) TGF-β1 signaling genes was altered in the marrow and spleen of PMF patients, respectively. Abnormalities included genes of TGF-β1 signaling, cell cycling and abnormal in chronic myeloid leukemia (EVI1 and p21(CIP)) (both marrow and spleen) and Hedgehog (marrow only) and p53 (spleen only) signaling. Pathway analyses of these alterations predict an increased osteoblast differentiation, ineffective hematopoiesis and fibrosis driven by non-canonical TGF-β1 signaling in marrow and increased proliferation and defective DNA repair in spleen. Since activation of non-canonical TGF-β1 signaling is associated with fibrosis in autoimmune diseases, the hypothesis that fibrosis in PMF results from an autoimmune process triggered by dead megakaryocytes was tested by determining that PMF patients expressed plasma levels of mitochondrial DNA and anti-mitochondrial antibodies greater than normal controls. These data identify autoimmunity as a possible cause of marrow fibrosis in PMF.
authors.affiliation: Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Ciaffoni
authors.affiliation: Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Cassella
authors.affiliation: Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Lilian
authors.initials: L
authors.lastname: Varricchio
authors.affiliation: Biotechnology Research Area, Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Massa
authors.affiliation: Biotechnology Research Area, Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy; Myeloproliferative Disease Research Consortium, New York, NY, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barosi
authors.affiliation: Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA; Myeloproliferative Disease Research Consortium, New York, NY, USA; Department of Biomedical Sciences, Alma Mater University, Bologna, Italy. Electronic address: annarita.migliaccio@mssm.edu.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Migliaccio
mesh_terms: D000328:Adult; D000818:Animals; D015551:Autoimmunity; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D055728:Primary Myelofibrosis / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000276:immunology*
chemical_list: D053773:Transforming Growth Factor beta1
keywords: Autoimmunity; Inflammation; Myelofibrosis; TGF-β1