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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4261-4268.
Prepublished online as a Blood First Edition Paper on September 8, 2005; DOI 10.1182/blood-2004-11-4468.
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Submitted November 23, 2004
Accepted July 18, 2005
mTOR regulates cell survival after etoposide treatment in primary AML cells
Qing Xu, James E Thompson, and Martin Carroll*
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA
* Corresponding author; email: carroll2{at}mail.med.upenn.edu.
Acute myeloid leukemia cells have constitutive activation of PI3 kinase and require PI3 kinase activation for survival, however the function of the PI3 kinase pathway in the survival of leukemic cells is poorly defined. We have studied the role of one PI3 kinase substrate, mTOR (mammalian target of rapamycin), in primary leukemic cells. In initial experiments, we have defined a novel growth media that improves survival of AML blasts in long term suspension culture and the survival of leukemic stem cells in short term cultures. Inhibition of mTOR using rapamycin leads to a modest decrease in cell survival after 2 days of incubation with more significant decrease in survival after 7 days of culture. However, when rapamycin is added to etoposide in 2 day cultures, there is a dramatic increase in the cytotoxicity of etoposide against AML blasts. Furthermore, etoposide consistently decreased the engraftment of AML cells in NOD/SCID animals and this effect was enhanced by co-incubation with rapamycin demonstrating that mTOR regulates survival of AML stem cells after etoposide treatment. These results suggest that rapamycin in combination with etoposide based chemotherapy may be efficacious in the treatment of AML.
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