Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia.

Lee K, Nam KT, Cho SH, Gudapati P, Hwang Y, Park DS, Potter R, Chen J, Volanakis E, Boothby M
J Exp Med. 2012 209 (4): 713-28

PMID: 22473959 · PMCID: PMC3328370 · DOI:10.1084/jem.20111470

Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-κB activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-κB activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-κB.

MeSH Terms (18)

Active Transport, Cell Nucleus Animals Carrier Proteins Cell Differentiation Cell Lineage Forkhead Box Protein O1 Forkhead Transcription Factors Mice Mice, Inbred C57BL NF-kappa B Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Pyruvate Dehydrogenase Acetyl-Transferring Kinase Rapamycin-Insensitive Companion of mTOR Protein Receptors, Notch Thymocytes TOR Serine-Threonine Kinases

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