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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3573-3580.
Prepublished online as a Blood First Edition Paper on August 3, 2004; DOI 10.1182/blood-2004-01-0193.
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Submitted January 16, 2004
Accepted July 18, 2004
Increased and pathological emperipolesis of neutrophils within megakaryocytes associated with marrow fibrosis in GATA-1low mice
Lucia Centurione, Angela Di Baldassarre, Maria Zingariello, Domenico Bosco, Valentina Gatta, Rosa Alba Rana, Vincenzo Langella, Antonio Di Virgilio, Alessandro M Vannucchi, and Anna Rita Migliaccio*
Department of Biomorphology, University G D'Annunzio, Chieti, Italy
Department of Biomedical Sciences, University G D'Annunzio, Chieti, Italy
CNR Institute for Organ Transplantation and Immunocytology, Chieti, Italy
Experimental Zooprophilac Institute G. Caporale, Chieti, Italy
Department of Hematology, University of Florence, Florence, Italy
Department of Security and Quality of Animal Experimentation, Istituto Superiore Sanita, Rome, Italy
Department of Clinical Biochemistry, Istituto Superiore Sanita, Rome, Italy
* Corresponding author; email: migliar{at}iss.it.
Deletion of megakaryocytic (Mk)-specific regulatory sequences of GATA-1 (Gata1tm2Sho or GATA-1low mutation) results in severe thrombocytopenia, because of defective thrombocytopoiesis, and myelofibrosis. As documented here, the GATA-1low mutation blocks Mk maturation between stage I and stage II, resulting in accumulation of defective Mk in the tissues of GATA-1low mice. The block in maturation includes failure to properly organize  -granules, since von Willebrand factor is barely detectable in mutant Mk and P-selectin, although normally expressed, is found frequently associated with the DMS instead than within granules. Conversely, both von Willebrand factor and P-selectin are barely detectable in GATA-1low platelets. Mutant Mk are surrounded by numerous myeloperoxidase-positive neutrophils, some of which appear in the process to establish contact with Mk by fusing their membrane with those of the DMS. As a result, 16% (in spleen) - 34% (in marrow) of GATA-1low Mk contain 1-3 neutrophils embedded in a vacuolated cytoplasm. The neutrophil-embedded GATA-1low Mk have morphological features (high electron density and negativity to TUNEL staining) compatible with those of cells dying from para-apotosis. We suggest that such an increased and pathological neutrophil emperipolesis may represent one of the mechanisms leading to myelofibrosis by releasing fibrogenic Mk cytokines and neutrophil proteases in the microenvironment.
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