However, clinically GC resistance occurs in 10-30% of untreated ALL patients and is more frequently seen in T-lineage ALL (T-ALL) than B-precursor ALL and GC resistance always leads to the failure of chemotherapy [4]. T-ALL is a highly malignant tumor representing 10%-15% of pediatric and 25% of adult ALL in humans and it is clinically regarded as a high-risk disease with a relapse rate of about 30% [5, 6]. T-ALL has a less favorable prognosis than B-cell ALL. The mechanisms that underlie the development

of GC resistance are poorly understood and likely vary with disease type, treatment regimen, and the genetic background of the patient [7]. However, an increasing number of reports indicate that activation of mammalian target of rapamycin see more (mTOR) signaling pathway may contribute to GC resistance in hematological malignancies [8–11]. A recent study, using a database of drug-associated gene expression profiles to screen for molecules whose selleck products profile overlapped with a gene expression signature phosphatase inhibitor of GC sensitivity/resistance in ALL cells, demonstrated that the mTOR inhibitor rapamycin profile matched the signature of GC sensitivity [12]. We recently demonstrated that nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), an oncogene originated from t(2;5)(p23;q35) in a subset of non-Hodgkin’s lymphoma transformed lymphoid

cells to become resistant to GC or Dex treatment by activating mTOR signaling pathway and rapamycin could re-sensitize the transformed lymphocytes to Dex treatment [13]. Rapamycin, the best studied mTOR inhibitor, was originally isolated from the soil bacterium Tau-protein kinase Streptomyces hygroscopicus in the mid-1970 s [14]. Although

it was initially developed as a fungicide and immunosuppressant, antitumor activity of rapamycin has been described in vitro and in vivo [15–18]. mTOR is a serine-threonine protein kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family. Inhibition of mTOR kinase leads to dephosphorylation of its two major downstream signaling components, p70 S6 kinase (p70S6K) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), which in turn inhibits the translation of specific mRNAs involved in cell cycle and proliferation and leads to G1 growth arrest [19, 20]. A major regulator of the mTOR pathway is the PI3K/AKT kinase cascade and activation of PI3K/AKT/mTOR has been found in lymphoid malignancies [21]. Most studies have shown that rapamycin acts as a cytostatic agent by arresting cells in the G1 phase [15–20]. Although cell cycle arrest can temporarily halt tumor progression, the affected clones could re-grow since the tumor cells have not been killed. Cell cycle inhibitor seems to work best in combination with chemotherapy. However, combination of cell cycle inhibitor with cytotoxic agents might be agonistic or antagonistic [22, 23].