Increased and pathologic emperipolesis of neutrophils within megakaryocytes associated with marrow fibrosis in GATA-1(low) mice

• Published in: Blood Vol. 104; no. 12; pp. 3573 - 3580
• Main Authors: Centurione, Lucia, Di Baldassarre, Angela, Zingariello, Maria, Bosco, Domenico, Gatta, Valentina, Rana, Rosa Alba, Langella, Vincenzo, Di Virgilio, Antonio, Vannucchi, Alessandro M, Migliaccio, Anna Rita
• Format: Journal Article
• Language: English
• Published: United States 01.12.2004
• Subjects: Animals; Antigens, Surface - analysis; Apoptosis; Bone Marrow Cells - pathology; Cell Fusion; Cytoplasm; DNA-Binding Proteins - physiology; Erythroid-Specific DNA-Binding Factors; GATA1 Transcription Factor; Megakaryocytes - pathology; Megakaryocytes - ultrastructure; Membrane Fusion; Mice; Mice, Mutant Strains; Microscopy, Electron; Neutrophils - pathology; Primary Myelofibrosis - etiology; Primary Myelofibrosis - pathology; Spleen - pathology; Transcription Factors - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-01-0193

Deletion of megakaryocytic-specific regulatory sequences of GATA-1 (Gata1(tm2Sho) or GATA-1(low) mutation) results in severe thrombocytopenia, because of defective thrombocytopoiesis, and myelofibrosis. As documented here, the GATA-1(low) mutation blocks megakaryocytic maturation between stage I and II, resulting in accumulation of defective megakaryocytes (MKs) in the tissues of GATA-1(low) mice. The block in maturation includes failure to properly organize alpha granules because von Willebrand factor is barely detectable in mutant MKs, and P-selectin, although normally expressed, is found frequently associated with the demarcation membrane system (DMS) instead of within granules. Conversely, both von Willebrand factor and P-selectin are barely detectable in GATA-1(low) platelets. Mutant MKs are surrounded by numerous myeloperoxidase-positive neutrophils, some of which appear in the process to establish contact with MKs by fusing their membrane with those of the DMS. As a result, 16% (in spleen) to 34% (in marrow) of GATA-1(low) MKs contain 1 to 3 neutrophils embedded in a vacuolated cytoplasm. The neutrophil-embedded GATA-1(low) MKs have morphologic features (high electron density and negativity to TUNEL staining) compatible with those of cells dying from para-apoptosis. We suggest that such an increased and pathologic neutrophil emperipolesis may represent one of the mechanisms leading to myelofibrosis by releasing fibrogenic MK cytokines and neutrophil proteases in the microenvironment.