Antileukemic activity of rapamycin in acute myeloid leukemia

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 acut...

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Bibliographic Details
Published in:	Blood 2005-03, Vol.105 (6), p.2527-2534
Main Authors:	Récher, Christian, Beyne-Rauzy, Odile, Demur, Cécile, Chicanne, Gaëtan, Dos Santos, Cédric, Mas, Véronique Mansat-De, Benzaquen, David, Laurent, Guy, Huguet, Françoise, Payrastre, Bernard
Format:	Article
Language:	eng
Subjects:	Adaptor Proteins, Signal Transducing - metabolism Adolescent Adult Aged Antibiotics, Antineoplastic - pharmacology Antineoplastic agents Biological and medical sciences Cell Cycle Proteins Chemotherapy Female G1 Phase - drug effects Hematologic and hematopoietic diseases Hematopoietic Stem Cells - metabolism Humans Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - metabolism Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Male Medical sciences Middle Aged Pharmacology. Drug treatments Phosphoproteins - metabolism Phosphorylation - drug effects Protein Kinases - metabolism Protein Processing, Post-Translational - drug effects Recurrence Resting Phase, Cell Cycle - drug effects Ribosomal Protein S6 Kinases, 70-kDa - metabolism Sirolimus - pharmacology TOR Serine-Threonine Kinases Tumor Cells, Cultured
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Summary:	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, 2 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 4 of 9 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.
ISSN:	0006-4971 1528-0020