Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

Proc Natl Acad Sci U S A. 2014 Mar 11;111(10):3805-10. doi: 10.1073/pnas.1320265111. Epub 2014 Feb 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Animals
  • Carrier Proteins / metabolism
  • Cell Cycle / immunology
  • Cell Cycle / physiology
  • DNA Primers
  • Flow Cytometry
  • Gene Expression Profiling
  • Immunoblotting
  • Immunohistochemistry
  • Lymphopoiesis / physiology*
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Models, Immunological*
  • Multiprotein Complexes / deficiency
  • Multiprotein Complexes / physiology*
  • Precursor Cells, T-Lymphoid / physiology*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / immunology*
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Regulatory-Associated Protein of mTOR
  • Signal Transduction / physiology
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / deficiency
  • TOR Serine-Threonine Kinases / metabolism*
  • TOR Serine-Threonine Kinases / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA Primers
  • Multiprotein Complexes
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • rictor protein, mouse
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Sirolimus