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Blood, 15 December 2008, Vol. 112, No. 13, pp. 5141-5149. Prepublished online as a Blood First Edition Paper on September 16, 2008; DOI 10.1182/blood-2008-03-146704. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-03-146704v1 112/13/5141    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 Hallaert, D. Y. Articles by Eldering, E. Search for Related Content PubMed PubMed Citation Articles by Hallaert, D. Y. Articles by Eldering, E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 21, 2008 Accepted August 8, 2008 c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL; Implications for therapeutic targeting of chemoresistant niches Delfine YH Hallaert, Annelieke Jaspers, Carel J van Noesel, Marinus HJ van Oers, Arnon P Kater, and Eric Eldering* Department of Hematology, Academic Medical Center, Amsterdam, Netherlands Department of Pathology, Academic Medical Center, Amsterdam, Netherlands Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands * Corresponding author; email: e.eldering{at}amc.uva.nl. In lymph node (LN) proliferation centers in chronic lymphocytic leukemia (CLL), the environment protects from apoptotic and cytotoxic triggers. Here, we aimed to define the molecular basis for the increased drug resistance and searched for novel strategies to circumvent it. The situation in CLL LN could be mimicked by prolonged in vitro CD40 stimulation, which resulted in upregulation of anti-apoptotic Bcl-xL, A1/Bfl-1 and Mcl-1 proteins, and afforded resistance to various classes of drugs (fludarabine, bortezomib, roscovitine). CD40 stimulation also caused ERK-dependent reduction of Bim-EL protein, but ERK inhibition did not prevent drug resistance. Drugs combined with sublethal doses of the BH3-mimetic ABT-737 displayed partial and variable effects per individual CD40-stimulated CLL. The anti-apoptotic profile of CD40-triggered CLL resembled BCR-Abl-dependent changes seen in CML, which prompted application of c-Abl inhibitors imatinib or dasatinib. Both compounds, but especially dasatinib, prevented the entire anti-apoptotic CD40 program in CLL cells, and restored drug sensitivity. These effects also occurred in CLL samples with dysfunctional p53. Importantly, ex vivo CLL LN samples also displayed strong ERK activation together with high Bcl-xL and Mcl-1 but low Bim levels. These data indicate that CLL cells in chemoresistant niches may be sensitive to therapeutic strategies that include c-Abl inhibitors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Dis-Abl-ing CD40 buys toxic assets John Gordon Blood 2008 112: 4787-4788. [Full Text] [PDF] This article has been cited by other articles: V. Pitini, C. Arrigo, and G. Altavilla Dasatinib induces a response in chronic lymphocytic leukemia Blood, January 8, 2009; 113(2): 498 - 498. [Full Text] [PDF]

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