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 HatakeyamaMasashi OhtaniYuko TadokoroKazuhito NakaTsuneo IkenoueTomokatsu IkawaHiroshi KawamotoHans Joerg FehlingKimi ArakiKen-ichi YamamuraSatoshi MatsudaAtsushi Hirao

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

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

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

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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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第10期|3805-3810|共6页
作者
Takayuki Hoshii; Atsuo Kasada; Tomoki HatakeyamaMasashi OhtaniYuko TadokoroKazuhito NakaTsuneo IkenoueTomokatsu IkawaHiroshi KawamotoHans Joerg FehlingKimi ArakiKen-ichi YamamuraSatoshi MatsudaAtsushi Hirao;
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作者单位

Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan;

Department of Cell Signaling, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 570-8506, Japan;

Division of Clinical Genome Research, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, JapanLaboratory for Lymphocyte Development, RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, JapanDepartment of Molecular Immunology, Institute of Immunology, University of Ulm, Ulm D-89081, GermanyDivision of Developmental Genetics, Center for Animal Resources and Development, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
complex; eradicates; leukemia;

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

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