Récher Christian, Beyne-Rauzy Odile, Demur Cécile, Chicanne Gaëtan, Dos Santos Cédric, Mas Véronique Mansat-De, Benzaquen David, Laurent Guy, Huguet Françoise, Payrastre Bernard
Institut National de la Santé et de la Recherche Médicale (Inserm) U563, CPTP, Département d'Oncogenèse et signalisation dans les cellules hématopoïétiques, IFR30, Toulouse, France.
Blood. 2005 Mar 15;105(6):2527-34. doi: 10.1182/blood-2004-06-2494. Epub 2004 Nov 18.
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.
雷帕霉素的哺乳动物靶点（mTOR）是多种细胞类型中生长和存活的关键调节因子。其组成性激活与多种癌症的发病机制有关。在本研究中，我们表明雷帕霉素抑制mTOR可通过阻断细胞周期的G0/G1期，强烈抑制最不成熟的急性髓系白血病（AML）细胞系的生长。相应地，在一系列23例AML病例中，mTOR的2个下游效应器4E-BP1和p70S6K以雷帕霉素敏感的方式被磷酸化。有趣的是，mTOR抑制剂显著损害新鲜AML细胞的克隆形成特性，同时保留正常造血祖细胞。此外，雷帕霉素在9例难治性/复发性初发AML或继发性AML患者中的4例中诱导了显著的临床反应。总体而言，我们的数据强烈表明，mTOR在大多数AML细胞中存在异常调节，并且雷帕霉素及其类似物通过靶向白血病克隆的克隆形成区室，可能用作AML治疗的新化合物。
