BclxL overexpression in megakaryocytes leads to impaired platelet fragmentation

被引:74
作者
Kaluzhny, Y
Yu, GG
Sun, SS
Toselli, PA
Nieswandt, B
Jackson, CW
Ravid, K
机构
[1] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA
[3] Univ Witten Herdecke, Dept Mol Oncol, Wuppertal, Germany
[4] St Jude Childrens Res Hosp, Div Exptl Hematol, Memphis, TN 38105 USA
关键词
D O I
10.1182/blood-2001-12-0263
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Fragmentation of polyploid megakaryocytes into platelets has great relevance for blood homeostasis. Apoptotic cell death is a highly regulated genetic program, which has been observed in mature megakaryocytes fragmenting into platelets. The antlapoptotic protein BclxL has been reported as up-regulated during megakaryocytic differentiation in vitro, but absent during late megakaryopoiesis. Our study focused on examining BclxL levels in megakaryocytes in vivo and in assessing the effect of its overexpression in transgenic mice (via the platelet factor 4 [PF4] promoter) on megakaryocyte development and platelet fragmentation. Interestingly, in the wild-type and less in PF4-driven transgenic mice, BclxL was not detected in a fraction of the large mature megakaryocytes, suggesting a regulation on the protein level. BclxL overexpression was associated with a moderate increase in megakaryocyte number, with no significant change in ploidy level or platelet counts. When the mice were challenged by induction of immune thrombocytopenia, the rate of platelet recovery was significantly slower in the transgenic mice as compared with controls. Moreover, proplatelet formation in vitro by transgenic megakaryocytes was limited. Transgenic megakaryocytes displayed poorly developed platelet demarcation membranes and cell margin extensions. Our study indicates that regulated expression of BclxL in megalkaryocytes is important for the development of cells with a high potential to fragment into platelets. (C) 2002 by The American Society of Hematology.
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页码:1670 / 1678
页数:9
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