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Blood, 1 January 2008, Vol. 111, No. 1, pp. 379-382. Prepublished online as a Blood First Edition Paper on September 18, 2007; DOI 10.1182/blood-2007-03-080796. This Article Full Text Full Text (PDF) Supplemental Methods and Tables All Versions of this Article: blood-2007-03-080796v1 111/1/379    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tamburini, J. Articles by Bouscary, D. Search for Related Content PubMed PubMed Citation Articles by Tamburini, J. Articles by Bouscary, D. Related Collections Brief Reports Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Brief Report Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways Jerome Tamburini1,4, Nicolas Chapuis1,3,5, Valérie Bardet1,3,5, Sophie Park1,4, Pierre Sujobert1,4, Lise Willems1,3, Norbert Ifrah6, François Dreyfus1,4, Patrick Mayeux1,3, Catherine Lacombe1,5, and Didier Bouscary1,4 1 Institut Cochin, Département d'Hématologie, Centre National de la Recherche Scientifique (Unité Mixte de Recherche 8104), Paris; 2 Inserm U567, Paris; 3 Université Paris Descartes, Faculté de Médecine René Descartes, Paris; 4 Service de Médecine Interne, UF d'Hématologie, Assistance Publique-Hôpitaux de Paris; Hôpital Cochin, Paris; 5 Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Paris; and 6 Service des Maladies du Sang, Centre Hospitalier Universitaire, Angers, France The phosphatidylinositol 3-kinase (PI3K)/Akt and mTORC1 pathways are frequently activated, representing potential therapeutic targets in acute myeloid leukemia (AML). In 19 AML samples with constitutive PI3K/Akt activation, the rapamycin derivative inhibitor everolimus (RAD001) increased Akt phosphorylation. This mTOR C1-mediated Akt up-regulation was explained by an insulin-like growth factor-1 (IGF-1)/IGF-1 receptor autocrine loop: (1) blast cells expressed functional IGF-1 receptors, and IGF-1-induced Akt activation was increased by RAD001, (2) a neutralizing anti-IGF-1R -IR3 monoclonal antibody reversed the RAD001-induced Akt phosphorylation, and (3) autocrine production of IGF-1 was detected in purified blast cells by quantitative reverse transcription-polymerase chain reaction and immunofluorescence. This RAD001-induced PI3K/Akt up-regulation was due to an up-regulated expression of the IRS2 adaptor. Finally, we observed that concomitant inhibition of mTORC1 and PI3K/Akt by RAD001 and IC87114 induced additive antiproliferative effects. Our results suggest that dual inhibition of the mTORC1 complex and the IGF-1/IGF-1R/PI3K/Akt pathway in AML may enhance the efficacy of mTOR inhibitors in treatment of this disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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