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Blood, 20 August 2009, Vol. 114, No. 8, pp. 1618-1627. Prepublished online as a Blood First Edition Paper on May 20, 2009; DOI 10.1182/blood-2008-10-184515. This Article Full Text Full Text (PDF) Supplemental Appendix and Figures All Versions of this Article: blood-2008-10-184515v1 114/8/1618    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 Google Scholar Articles by Tamburini, J. Articles by Bouscary, D. PubMed PubMed Citation Articles by Tamburini, J. Articles by Bouscary, D. Related Collections Myeloid Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia Jerome Tamburini13, Alexa S. Green1,2, Valerie Bardet1,2,4, Nicolas Chapuis1,2,4, Sophie Park13, Lise Willems1,2, Madalina Uzunov5, Norbert Ifrah6, François Dreyfus13, Catherine Lacombe1,2,4, Patrick Mayeux1,2, and Didier Bouscary13 1 Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS, UMR8104), Paris; 2 Inserm U567, Paris; 3 Service de Médecine Interne-UF d'Hématologie, Assistance Publique-Hopitaux de Paris (AP-HP), 4 Service d'Hématologie Biologique, APHP, Hôpital Cochin, Paris; 5 Service d'hématologie, Hôpital de la Pitié-Salpêtrière, Paris; and 6 Service des Maladies du Sang, Centre Hospitalier Universitaire (CHU) Angers, France The deregulation of translation markedly contributes to the malignant phenotype in cancers, and the assembly of the translation initiating complex eIF4F is the limiting step of this process. The mammalian Target of Rapamycin Complex 1 (mTORC1) is thought to positively regulate eIF4F assembly and subsequent oncogenic protein synthesis through 4E-BP1 phosphorylation. We showed here that the translation inhibitor 4EGI-1 decreased the clonogenic growth of leukemic progenitors and induced apoptosis of blast cells, with limited toxicity against normal hematopoiesis, which emphasize the importance of translation deregulation in acute myeloid leukemia (AML) biology. However, the mTORC1 inhibitor RAD001 (a rapamycin derivate) did not induce AML blast cell apoptosis. We herein demonstrated that mTORC1 disruption using raptor siRNA or RAD001 failed to inhibit 4E-BP1 phosphorylation in AML. Moreover, RAD001 failed to inhibit eIF4F assembly, to decrease the proportion of polysome-bound c-Myc mRNA, and to reduce the translation-dependent accumulation of oncogenic proteins. We identified the Pim-2 serine/threonine kinase as mainly responsible for 4E-BP1 phosphorylation on the S65 residue and subsequent translation control in AML. Our results strongly implicate an mTORC1-independent deregulation of oncogenic proteins synthesis in human myeloid leukemogenesis. Direct inhibition of the translation initiating complex thus represents an attractive option for the development of new therapies in AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Taking aim at protein translation in AML Martin Carroll Blood 2009 114: 1458-1459. [Abstract] [Full Text] [PDF] This article has been cited by other articles: M. Carroll Taking aim at protein translation in AML Blood, August 20, 2009; 114(8): 1458 - 1459. [Abstract] [Full Text] [PDF]

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