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 (
IntroductionAcute myeloid leukemia (AML) is a clonal disorder characterized by accumulation of malignant hematopoietic progenitor cells (HPCs) with impaired differentiation program. Despite important progress in the therapy of AML and high rates of complete remission after induction chemotherapy, most patients will relapse and die from the disease. Prevention of relapse is based on intensified programs, including high-dose chemotherapy and autologous or allogenic transplants that can benefit young patients. Thus, outcome of patients older than 60 years has not been improved for decades, underlying the need for potent and less toxic drugs for the treatment of this disease. 1 Recent studies have demonstrated that AML cells are characterized by recurrent mutations of genes involved in cell differentiation, survival, and proliferation. A pathogenesis model for AML suggests that mutations of both tyrosine kinase receptors and transcription factors, by conferring survival and/or proliferative advantage (class I mutation) and by impairing cell differentiation (class II mutation), are needed to cause leukemia. 2 Fms-like tyrosine kinase 3 (FLT3), c-KIT, and RAS mutations occur in 50% to 60% of AML cases, 3-7 leading to aberrant activation of major cell survival or proliferation pathways such as mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/ Akt, signal transducer and activator of transcription (STAT), or nuclear factor B (NF-kB). [8][9][10] These antiapoptotic signaling pathways also contribute to AML resistance to the cytotoxic agents currently used in this disease. 11,12 Thus, therapeutic interference with these pathways represents an attractive strategy in AML therapy. In this context, current clinical trials are evaluating new compounds directly targeting RAS or FLT3 (eg, farnesyl transferase inhibitors; CEP-701 and PKC 412). 13,14 Molecules integrating multiple signal transduction pathways may represent relevant therapeutic targets in AML. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in the regulation of cell growth and proliferation by translational control of key proteins such as the cyclin-dependent kinase (CDK) inhibitor p27kip1, retinoblastoma protein, cyclin D1, c-myc, or STAT 3. mTOR is activated by different stimuli including nutrients or growth factors. 15,16 Once activated, mTOR can phosphorylate its downstream targets, the ribosomal p70S6 kinase (p70S6K) and the 4E-binding protein 1 (4E-BP1). There are 2 known isoforms of S6K, p70 and p85, generated from differential splicing from a common gene. The p85S6K isoform is identical to p70S6K, except for a 23-amino acid extension at the amino-terminus that specifically targets it to ...
