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Transgenic mice overexpressing human c-mpl ligand exhibit chronic
thrombocytosis and display enhanced recovery from 5-fluorouracil or
antiplatelet serum treatment
W Zhou, CF Toombs, T Zou, J Guo and MO Robinson
Amgen Inc, Thousand Oaks, CA 91320, USA.
The consequences of long-term in vivo expression of human c-mpl ligand in a
mouse model were examined. Transgenic mice expressing the human full-length
cDNA in the liver exhibited a fourfold increase in circulating platelet
count that persisted stably over the life of the animals. Transgenic
animals thrived and appeared healthy for at least 500 days. Transgenic
platelets appeared normal with respect to surface antigens and response to
platelet aggregation agonists. The highest- expressing transgenic line
maintained human c-mpl ligand serum levels of 3 ng/mL. Megakaryocyte
numbers in bone marrow and spleen were elevated, as were bone marrow and
spleen megakaryocyte colony-forming cells (MEG-CFC). Megakaryocytes were
observed in the bone marrow, spleen, liver, and lung, but in no other
sites. Circulating myeloid and lymphoid cell populations were increased
twofold. Additionally, the animals had a slight but significant anemia
despite an increase in marrow colony-forming units-erythroid (CFU-E). No
evidence of myelofibrosis was observed in the bone marrow. The platelet
nadir in response to administration of either antiplatelet serum (APS) or
5- fluorouracil (5FU) was significantly reduced relative to the control
level. Furthermore, the red blood cell (RBC) nadir was reduced relative to
control levels in both models, suggesting that c-mpl ligand can directly or
indirectly support the maintenance of erythrocyte levels following
thrombopoietic insult.
Volume 89,
Issue 5,
pp. 1551-1559,
03/01/1997
Copyright © 1997 by The American Society of Hematology
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