MTOR complex 2 mediates Notch signaling in thymocyte and T-cell leukemia development (64.8)

Abstract

Abstract Mammalian target of rapamycin (mTOR) is an important component of the PI3-kinase (PI3K) pathway that regulates cell growth and proliferation. PI3K signaling cascades can be initiated by activation of Notch, a critical regulator for T lineage commitment and leukemia development. Here we show that mTOR complex 2 (mTORC2) is functionally vital as a downstream target of Notch in thymocytes and T-cell acute lymphoblastic leukemia (T-ALL). Conditional deletion of rictor, an essential component of mTORC2, results in impaired proliferation and differentiation of pre-T cells driven by Notch ligation. Moreover, mTORC2 is a primary kinase for Akt S473 and enhances Akt activity in thymocytes. Furthermore, mTORC2 regulates NF-κB activity, such that constitutively active Akt can restore nuclear NF-κB levels in the rictor-depleted pre-T cells, as well as normalizing Notch-initiated proliferation and differentiation. Strikingly, interruption of mTORC2 significantly delays T-ALL induced by Notch1 activating mutation and suppresses infiltration of leukemic cells into the non-lymphoid organs. Our study provides evidence of a key role of mTORC2 in relaying Notch signaling in thymocyte development, and reveals that mTORC2 promotes Notch-driven leukemia progression.