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

Takayuki Hoshii, Atsuo Kasada, Tomoki Hatakeyama, Masashi Ohtani, Yuko Tadokoro, Kazuhito Naka, Tsuneo Ikenoue, Tomokatsu Ikawa, Hiroshi Kawamoto, Hans Joerg Fehling, Kimi Araki, Ken Ichi Yamamura, Satoshi Matsuda, Atsushi Hirao

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3805-3810
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number10
DOIs
Publication statusPublished - 11-03-2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

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