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Blood, 1 February 2006, Vol. 107, No. 3, pp. 1149-1155. Prepublished online as a Blood First Edition Paper on September 29, 2005; DOI 10.1182/blood-2005-05-1935. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-05-1935v1 107/3/1149    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Teachey, D. T. Articles by Grupp, S. A. Search for Related Content PubMed PubMed Citation Articles by Teachey, D. T. Articles by Grupp, S. A. Related Collections Neoplasia Apoptosis Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL David T. Teachey, Dana A. Obzut, Jonathan Cooperman, Junjie Fang, Martin Carroll, John K. Choi, Peter J. Houghton, Valerie I. Brown, and Stephan A. Grupp From the Division of Oncology, Department of Pediatrics, and the Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, PA; the Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA; and the Department of Molecular Pharmacology, St Jude Children's Research Hospital, Memphis, TN. Acute lymphoblastic leukemia (ALL) in adult patients is often resistant to current therapy, making the development of novel therapeutic agents paramount. We investigated whether mTOR inhibitors (MTIs), a class of signal transduction inhibitors, would be effective in primary human ALL. Lymphoblasts from adult patients with precursor B ALL were cultured on bone marrow stroma and were treated with CCI-779, a second generation MTI. Treated cells showed a dramatic decrease in cell proliferation and an increase in apoptotic cells, compared to untreated cells. We also assessed the effect of CCI-779 in a NOD/SCID xenograft model. We treated a total of 68 mice generated from the same patient samples with CCI-779 after establishment of disease. Animals treated with CCI-779 showed a decrease in peripheral-blood blasts and in splenomegaly. In dramatic contrast, untreated animals continued to show expansion of human ALL. We performed immunoblots to validate the inhibition of the mTOR signaling intermediate phospho-S6 in human ALL, finding down-regulation of this target in xenografted human ALL exposed to CCI-779. We conclude that MTIs can inhibit the growth of adult human ALL and deserve close examination as therapeutic agents against a disease that is often not curable with current therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. A. Lopez-Lago, T. Okada, M. M. Murillo, N. Socci, and F. G. Giancotti Loss of the Tumor Suppressor Gene NF2, Encoding Merlin, Constitutively Activates Integrin-Dependent mTORC1 Signaling Mol. Cell. Biol., August 1, 2009; 29(15): 4235 - 4249. [Abstract] [Full Text] [PDF] P. R. Hagner, K. Mazan-Mamczarz, B. Dai, S. Corl, X. F. Zhao, and R. B. Gartenhaus Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction Blood, May 28, 2009; 113(22): 5526 - 5535. [Abstract] [Full Text] [PDF] R. Crazzolara, A. Cisterne, M. Thien, J. Hewson, R. Baraz, K. F. Bradstock, and L. J. 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