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(American Journal of Pathology. 2005;167:849-858.)
© 2005 American Society for Investigative Pathology

Abnormalities of GATA-1 in Megakaryocytes from Patients with Idiopathic Myelofibrosis

Alessandro M. Vannucchi^*, Alessandro Pancrazzi^*, Paola Guglielmelli^*, Simonetta Di Lollo, Costanza Bogani^*, Gianna Baroni, Lucia Bianchi^*, Anna Rita Migliaccio, Alberto Bosi^* and Francesco Paoletti^||

From the Departments of Hematology,^* Human Pathology and Oncology, and Experimental Pathology and Oncology,^|| University of Florence, Florence, Italy; the Department of Hematology, Oncology, and Molecular Medicine, Istituto Superiore Sanità, Rome, Italy; and the Department of Pathology, University of Illinois at Chicago, Chicago, Illinois

The abnormal megakaryocytopoiesis associated with idiopathic myelofibrosis (IM) plays a role in its pathogenesis. Because mice with defective expression of transcription factor GATA-1 (GATA-1^low mutants) eventually develop myelofibrosis, we investigated the occurrence of GATA-1 abnormalities in IM patients. CD34⁺ cells were purified from 12 IM patients and 8 controls; erythroblasts and megakaryocytes were then obtained from unilineage cultures of CD34⁺ cells. Purified CD61⁺, GPA⁺, and CD34⁺ cells from IM patients contained levels of GATA-1, GATA-2, and FOG-1 mRNA, as well as of GATA-2 protein, that were similar to controls. In contrast, CD61⁺ cells from IM patients contained significantly reduced GATA-1 protein. Furthermore, 45% of megakaryocytes in biopsies from IM patients did not stain with anti-GATA-1 antibody, as compared to controls (2%), essential thrombocythemia (4%), or polycythemia vera (11%) patients. Abnormalities in immunoreactivity for FOG-1 were not found, and no mutations in GATA-1 coding sequences were found. The presence of GATA-1^neg megakaryocytes in bone marrow biopsies was independent of the Val617Phe JAK2 mutation, making it unlikely that a downstream functional relationship exists. We conclude that megakaryocytes from IM patients have reduced GATA-1 content, possibly contributing to disease pathogenesis as in the GATA-1^low mice and also representing a novel IM-associated marker.

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