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Blood, 1 March 2006, Vol. 107, No. 5, pp. 2094-2097. Prepublished online as a Blood First Edition Paper on November 22, 2005; DOI 10.1182/blood-2005-08-3317. This Article Full Text (PDF) Supplemental Table All Versions of this Article: 2005-08-3317v1 107/5/2094    most recent Alert me when this article is cited Alert me if a correction is posted 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 Cai, D. Articles by Burchert, A. Search for Related Content PubMed PubMed Citation Articles by Cai, D. Articles by Burchert, A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 16, 2005 Accepted October 25, 2005 FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment Dali Cai, Ying Wang, Oliver G Ottmann, Peter J Barth, Andreas Neubauer, and Andreas Burchert* Onkologie und Immunologie, Universitatsklinikum Marburg und GieBen, Standort Marburg, Klinik fur Hamatologie, Marburg, Germany Medizinische Klinik III, University Hospital Frankfurt, Frankfurt, Germany Universitatsklinikum Marburg und GieBen, Institut fur Pathologie, Marburg, Germany * Corresponding author; email: burchert{at}staff.uni-marburg.de. Leukemias are differentially sensitive to histone deacytelase inhibitor (HDI)-induced apoptosis, but molecular reasons for this remain unclear. We here show that BCR/ABL-, but not FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)- transformed 32D-cells or primary acute myeloid leukemia (AML) blasts undergo apoptosis after treatment with the HDI valproic acid (VPA) plus ATRA (VPA/ATRA). A particular VPA/ATRA responsiveness of Philadelphia chromosome positive (Ph+) acute lymphatic leukemia (ALL) was confirmed in a therapy-refractory patient in vivo. HDI-stimulated apoptosis in Ph+-cells was caspase-dependent, but independent from Akt-pathway inhibition. Conversely, separate blockage of the Akt/mTor-signaling pathway was a conditio sine qua non for overcoming apoptosis resistance to VPA/ATRA in FLT3-ITD-cells, and primary AML blasts (n=9). In conclusion, constitutive Akt-activation causes apoptosis resistance to VPA/ATRA in AML, but not in Ph+-leukemia. This warrants the application of HDI-based therapies in poor risk Ph+-ALL, and the use of Akt/mTor-inhibitors to overcome HDI-resistance in AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Wang, D. Cai, C. Brendel, C. Barett, P. Erben, P. W. Manley, A. Hochhaus, A. Neubauer, and A. Burchert Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation Blood, March 1, 2007; 109(5): 2147 - 2155. [Abstract] [Full Text] [PDF] S. Knapper, K. I. Mills, A. F. Gilkes, S. J. Austin, V. Walsh, and A. K. Burnett The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases Blood, November 15, 2006; 108(10): 3494 - 3503. [Abstract] [Full Text] [PDF]

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