Notch1 Transcriptionally Activates Deptor And Promotes Akt Activation In Acute T-Cell Lymphoblastic Leukemia

Acute T-cell lymphoblastic leukemia (T-ALL) is a malignant disorder of thymocyte progenitors, accounting for 10-15% of pediatric acute lymphoblastic leukemia. The activation of NOTCH1 signaling in T-ALL, by either NOTCH1 (Weng A et al, Science, 2004) or FBW7 (Thompson BJ, J Exp Med, 2007) mutations, is one of the major events that contribute to disease development. DEPTOR emerges as an endogenous mTOR inhibitor, whose expression is low in most cancer cells but surprisingly high in multiple myeloma, resulting in activated AKT (Peterson TR et al, Cell, 2009). However, its implications in other hematological malignancies and the mechanism of regulation remains largely unknown. In this study, we present a novel NOTCH1-mediated transcriptional regulation of DEPTOR in T-ALL and show that DEPTOR is required for T-ALL cell proliferation and survival, and regulates T-ALL cell glucose metabolism via AKT activation.