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Blood, 5 March 2009, Vol. 113, No. 10, pp. 2302-2311. Prepublished online as a Blood First Edition Paper on December 8, 2008; DOI 10.1182/blood-2008-07-167023. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-07-167023v1 113/10/2302    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 Nordigården, A. Articles by Jönsson, J.-I. Search for Related Content PubMed PubMed Citation Articles by Nordigården, A. Articles by Jönsson, J.-I. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor–induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3 Amanda Nordigården1,*, Maria Kraft1,*, Pernilla Eliasson1,*, Verena Labi2, Eric W.-F. Lam3, Andreas Villunger2, and Jan-Ingvar Jönsson1 1 Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; 2 Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria; and 3 Cancer Research-UK Labs, Department of Oncology, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom Constitutively activating internal tandem duplications (ITD) of FLT3 (FMS-like tyrosine kinase 3) are the most common mutations in acute myeloid leukemia (AML) and correlate with poor prognosis. Receptor tyrosine kinase inhibitors targeting FLT3 have developed as attractive treatment options. Because relapses occur after initial responses, identification of FLT3-ITD–mediated signaling events are important to facilitate novel therapeutic interventions. Here, we have determined the growth-inhibitory and proapototic mechanisms of 2 small molecule inhibitors of FLT3, AG1295 or PKC412, in hematopoietic progenitor cells, human leukemic cell lines, and primary AML cells expressing FLT3-ITD. Inactivation of the PI3-kinase pathway, but not of Ras–mitogen-activated protein (MAP) kinase signaling, was essential to elicit cytotoxic responses. Both compounds induced up-regulation of proapoptotic BH3-only proteins Bim and Puma, and subsequent cell death. However, only silencing of Bim, or its direct transcriptional activator FOXO3a, abrogated apoptosis efficiently. Similar findings were made in bone marrow cells from gene-targeted mice lacking Bim and/or Puma infected with FLT3-ITD and treated with inhibitor, where loss of Puma only provided transient protection from apoptosis, but loss of Bim preserved clonal survival upon FLT3-ITD inhibition. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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