title: Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells.
abstract: mTOR is an evolutionarily conserved kinase that plays a critical role in sensing and responding to environmental determinants. Recent studies have shown that fine-tuning of the activity of mTOR complexes contributes to organogenesis and tumorigenesis. Although rapamycin, an allosteric mTOR inhibitor, is an effective immunosuppressant, the precise roles of mTOR complexes in early T-cell development remain unclear. Here we show that mTORC1 plays a critical role in the development of both early T-cell progenitors and leukemia. Deletion of Raptor, an essential component of mTORC1, produced defects in the earliest development of T-cell progenitors in vivo and in vitro. Deficiency of Raptor resulted in cell cycle abnormalities in early T-cell progenitors that were associated with instability of the Cyclin D2/D3-CDK6 complexes; deficiency of Rictor, an mTORC2 component, did not have the same effect, indicating that mTORC1 and -2 control T-cell development in different ways. In a model of myeloproliferative neoplasm and T-cell acute lymphoblastic leukemia (T-ALL) evoked by Kras activation, Raptor deficiency dramatically inhibited the cell cycle in oncogenic Kras-expressing T-cell progenitors, but not myeloid progenitors, and specifically prevented the development of T-ALL. Although rapamycin treatment significantly prolonged the survival of recipient mice bearing T-ALL cells, rapamycin-insensitive leukemia cells continued to propagate in vivo. In contrast, Raptor deficiency in the T-ALL model resulted in cell cycle arrest and efficient eradication of leukemia. Thus, understanding the cell-context-dependent role of mTORC1 illustrates the potential importance of mTOR signals as therapeutic targets.
authors.affiliation: Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hoshii
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kasada
authors.forename: Tomoki
authors.initials: T
authors.lastname: Hatakeyama
authors.forename: Masashi
authors.initials: M
authors.lastname: Ohtani
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tadokoro
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Naka
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ikenoue
authors.forename: Tomokatsu
authors.initials: T
authors.lastname: Ikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.forename: Hans Joerg
authors.initials: HJ
authors.lastname: Fehling
authors.forename: Kimi
authors.initials: K
authors.lastname: Araki
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000276:immunology / Q000502:physiology; D017931:DNA Primers; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015151:Immunoblotting; D007150:Immunohistochemistry; D038041:Lymphopoiesis / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D018448:Models, Immunological; D046912:Multiprotein Complexes / Q000172:deficiency / Q000502:physiology*; D054504:Precursor Cells, T-Lymphoid / Q000502:physiology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D017931:DNA Primers; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; C525637:rictor protein, mouse; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus