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

• Published in: The American journal of pathology Vol. 167; no. 3; pp. 849 - 858
• Main Authors: Vannucchi, Alessandro M., Pancrazzi, Alessandro, Guglielmelli, Paola, Di Lollo, Simonetta, Bogani, Costanza, Baroni, Gianna, Bianchi, Lucia, Migliaccio, Anna Rita, Bosi, Alberto, Paoletti, Francesco
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.09.2005; ASIP; American Society for Investigative Pathology
• Subjects: Antibodies - metabolism; Biological and medical sciences; Case-Control Studies; Cells, Cultured; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; Erythroid-Specific DNA-Binding Factors; Female; GATA1 Transcription Factor; Hematologic and hematopoietic diseases; Humans; Immunohistochemistry - methods; Integrin beta3 - metabolism; Investigative techniques, diagnostic techniques (general aspects); Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Megakaryocytes - metabolism; Megakaryocytes - pathology; Original Research Paper; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Polycythemia Vera - metabolism; Polycythemia Vera - pathology; Primary Myelofibrosis - metabolism; Primary Myelofibrosis - pathology; Staining and Labeling; Thrombocytosis - metabolism; Thrombocytosis - pathology; Transcription Factors - deficiency; Transcription Factors - immunology; Transcription Factors - metabolism; Human; Myeloproliferative syndrome; Signal transduction; Anatomic pathology; Myelofibrosis; Megakaryocyte; Hemopathy; Anomaly; Transcription factor GATA1
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)62056-1

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.