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 Blood, 15 April 2007, Vol. 109, No. 8, pp. 3509-3512.
Prepublished online as a Blood First Edition Paper on December 19, 2006; DOI 10.1182/blood-2006-06-030833.

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NEOPLASIA

Brief Report

Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML

Zhihong Zeng1, Dos D. Sarbassov2,3, Ismael J. Samudio1, Karen W. L. Yee4, Mark F. Munsell5, C. Ellen Jackson1, Francis J. Giles4, David M. Sabatini2,3, Michael Andreeff1,4, and Marina Konopleva1

1 Section of Molecular Hematology and Therapy, Departments of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 2 Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, MA; 3 Department of Biochemistry, The Broad Institute, Cambridge, MA; 4 Section of Molecular Hematology and Therapy, Departments of Leukemia and 5 Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX

The mTOR complex 2 (mTORC2) containing mTOR and rictor is thought to be rapamycin insensitive and was recently shown to regulate the prosurvival kinase AKT by phosphorylation on Ser473. We investigated the molecular effects of mTOR inhibition by the rapamycin derivatives (RDs) temsirolimus (CCI-779) and everolimus (RAD001) in acute myeloid leukemia (AML) cells. Unexpectedly, RDs not only inhibited the mTOR complex 1 (mTORC1) containing mTOR and raptor with decreased p70S6K, 4EPB1 phosphorylation, and GLUT1 mRNA, but also blocked AKT activation via inhibition of mTORC2 formation. This resulted in suppression of phosphorylation of the direct AKT substrate FKHR and decreased transcription of D-cyclins in AML cells. Similar observations were made in samples from patients with hematologic malignancies who received RDs in clinical studies. Our study provides the first evidence that rapamycin derivatives inhibit AKT signaling in primary AML cells both in vitro and in vivo, and supports the therapeutic potential of mTOR inhibition strategies in leukemias.


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