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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2001-12-0263.
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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1670-1678
HEMATOPOIESIS
BclxL overexpression in megakaryocytes leads to impaired platelet
fragmentation
Yulia Kaluzhny,
Guangyao Yu,
Shishinn Sun,
Paul A. Toselli,
Bernhard Nieswandt,
Carl W. Jackson, and
Katya Ravid
From the Department of Biochemistry and Whittaker
Cardiovascular Institute, Boston University School of Medicine, MA;
Department of Molecular Oncology, Witten/Herdecke University,
Wuppertal, Germany; and Division of Experimental Hematology, St
Jude Children's Research Hospital, Memphis, TN.
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 antiapoptotic 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 megakaryocytes is important for
the development of cells with a high potential to fragment into platelets.
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