Increased and pathologic emperipolesis of neutrophils within megakaryocytes associated with marrow fibrosis in GATA-1low mice
Increased and pathologic emperipolesis of neutrophils within megakaryocytes associated with marrow fibrosis in GATA-1low mice
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DOI：
10.1182/blood-2004-01-0193
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发表时间：
2004-12-01
期刊：
影响因子：
20.3
通讯作者：
Migliaccio, AR
中科院分区：
文献类型：
--
作者：
Centurione, L;Di Baldassarre, A;Migliaccio, AR
GATA-1的巨核细胞特异性调控序列(GATA1(Tm2Sho)或GATA-1(Low)突变)的缺失会导致严重的血小板减少，原因是有缺陷的血小板生成和骨髓纤维化。如本文所述，GATA-1(低)突变阻止了第一和第二阶段之间的巨核细胞成熟，导致有缺陷的巨核细胞(MKS)在GATA-1(低)小鼠的组织中积累。成熟过程中的障碍包括未能正确组织颗粒，因为von Willebrand因子在突变的MKs中几乎检测不到，而P-选择素虽然正常表达，但经常被发现与分界膜系统(DMS)有关，而不是在颗粒内。相反，von Willebrand因子和P-选择素在GATA-1(低)血小板中几乎检测不到。突变的MKS被大量髓过氧化物酶阳性的中性粒细胞包围，其中一些出现在与DMS的膜融合的过程中与MKS建立联系的过程中。其结果是，16%(在脾)到34%(在骨髓)的GATA-1(低)巨噬细胞含有1到3个中性粒细胞包埋在空泡化的细胞质中。中性粒细胞包埋的GATA-1(低)MKs的形态特征(高电子密度和TUNEL染色阴性)与死于类凋亡的细胞的形态特征相一致。我们认为，这种病理性的中性粒细胞增多可能是导致骨髓纤维化的机制之一，它通过在微环境中释放纤维性的MK细胞因子和中性粒细胞蛋白酶而导致。(C)2004年，由美国血液病学会提供。
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 a 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. (C) 2004 by The American Society of Hematology.