title: Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia.
abstract: 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.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Keunwook
authors.initials: K
authors.lastname: Lee
authors.forename: Ki Taek
authors.initials: KT
authors.lastname: Nam
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Cho
authors.forename: Prathyusha
authors.initials: P
authors.lastname: Gudapati
authors.forename: Yoonha
authors.initials: Y
authors.lastname: Hwang
authors.forename: Do-Sim
authors.initials: DS
authors.lastname: Park
authors.forename: Ross
authors.initials: R
authors.lastname: Potter
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Volanakis
authors.forename: Mark
authors.initials: M
authors.lastname: Boothby
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D002454:Cell Differentiation; D019070:Cell Lineage; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051880:Receptors, Notch / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D060168:Thymocytes / Q000166:cytology*
chemical_list: D002352:Carrier Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D016328:NF-kappa B; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051880:Receptors, Notch; C525637:rictor protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases