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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1278-1285.
Prepublished online as a Blood First Edition Paper on October 23, 2003; DOI 10.1182/blood-2003-06-2158.
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HEMATOPOIESIS
BUBR1 deficiency results in abnormal megakaryopoiesis
Qi Wang,
Tongyi Liu,
Yuqiang Fang,
Suqing Xie,
Xuan Huang,
Radma Mahmood,
Gita Ramaswamy,
Kathleen M. Sakamoto,
Zbigniew Darzynkiewicz,
Ming Xu, and
Wei Dai
From the Division of Molecular Carcinogenesis, Department of Medicine, Brander Cancer Institute, and Department of Pathology, New York Medical College, Valhalla, NY; Core Facility for Histopathology, Albert Einstein College of Medicine, Bronx, NY; Division of Hematology-Oncology, Mattel Children's Hospital, Department of Pathology and Laboratory Medicine, University of California at Los Angeles (UCLA) Jonsson Comprehensive Cancer Center, Molecular Biology Institute, David Geffen School of Medicine, Los Angeles, CA; and Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH.
The physiologic function of BUBR1, a key component of the spindle checkpoint, was examined by generating BUBR1-mutant mice. BUBR1/ embryos failed to survive beyond day 8.5 in utero as a result of extensive apoptosis. Whereas BUBR1+/ blastocysts grew relatively normally in vitro, BUBR1/ blastocysts exhibited impaired proliferation and atrophied. Adult BUBR1+/ mice manifested splenomegaly and abnormal megakaryopoiesis. BUBR1 haploinsufficiency resulted in an increase in the number of splenic megakaryocytes, which was correlated with an increase in megakaryocytic, but a decrease in erythroid, progenitors in bone marrow cells. RNA interferencemediated down-regulation of BUBR1 also caused an increase in polyploidy formation in murine embryonic fibroblast cells and enhanced megakaryopoiesis in bone marrow progenitor cells. However, enhanced megakaryopoiesis in BUBR1+/ mice was not correlated with a significant increase in platelets in peripheral blood, which was at least partly due to a defect in the formation of proplatelet-producing megakaryocytes. Together, these results indicate that BUBR1 is essential for early embryonic development and normal hematopoiesis.

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