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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2527-2534.
Prepublished online as a Blood First Edition Paper on November 18, 2004; DOI 10.1182/blood-2004-06-2494.
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Submitted July 1, 2004
Accepted November 8, 2004
Anti-leukemic activity of rapamycin in acute myeloid leukemia
Christian Recher*, Odile Beyne-Rauzy, Cecile Demur, Gaetan Chicanne, Cedric Dos Santos, Veronique Mansat-De Mas, David Benzaquen, Guy Laurent, Francoise Huguet, and Bernard Payrastre
CPTP, Departement d'Oncogenese et signalisation dans les cellules hematopoietiques, IFR30, Inserm U563, Toulouse, France; Service d'Hematologie, Centre Hospitalier Universitaire Purpan, Toulouse, France
CPTP, Departement d'Oncogenese et signalisation dans les cellules hematopoietiques, IFR30, Inserm U563, Toulouse, France
CPTP, Departement d'Oncogenese et signalisation dans les cellules hematopoietiques, IFR30, Inserm U563, Toulouse, France; Laboratoire d'Hematologie, Centre Hospitalier Universitaire Purpan, Toulouse, France
Service d'Orthopedie, Centre Hospitalier Universitaire Purpan, Toulouse, France
Service d'Hematologie, Centre Hospitalier Universitaire Purpan, Toulouse, France
* Corresponding author; email: recher.c{at}chu-toulouse.fr.
The mammalian Target of Rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, two downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in four out of nine patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.
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