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Blood, 1 January 2009, Vol. 113, No. 1, pp. 149-153. Prepublished online as a Blood First Edition Paper on October 3, 2008; DOI 10.1182/blood-2008-02-138560. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2008-02-138560v1 113/1/149    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 Citing Articles via Google Scholar Google Scholar Articles by Balakrishnan, K. Articles by Gandhi, V. Search for Related Content PubMed PubMed Citation Articles by Balakrishnan, K. Articles by Gandhi, V. Related Collections Lymphoid Neoplasia Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Brief Report AT-101 induces apoptosis in CLL B cells and overcomes stromal cell–mediated Mcl-1 induction and drug resistance Kumudha Balakrishnan1, Jan A. Burger2, William G. Wierda2, and Varsha Gandhi1,2 Departments of 1 Experimental Therapeutics and 2 Leukemia, University of Texas M. D. Anderson Cancer Center, Houston Resistance to apoptosis in CLL B cells is associated with overexpression of Bcl-2 family antiapoptotic proteins. Their expression is endogenous, but is also induced by signals from the microenvironment resulting in intrinsic and extrinsic drug resistance. Because AT-101 binds to the BH3 motif of all Bcl-2–family antiapoptotic proteins, we hypothesized that this molecule could overcome resistance. AT-101 treatment (20 µM for 24 hours) resulted in a median 72% apoptosis in CLL cells (patients; n = 32, P < .001). Stromal cells protected CLL B cells from spontaneous and fludarabine-induced apoptosis (P = .003) by increasing the Mcl-1 protein levels. However, AT-101 induced similar extent of down-regulation of Mcl-1 and apoptosis in CLL lymphocytes cultured in suspension or on stroma (P = .999). Stromal cells expressed undetectable levels of antiapoptotic but high levels of activated ERK and AKT proteins and had low or no apoptosis with AT-101. Collectively, these data demonstrate that AT-101 induces apoptosis in CLL B cells and overcomes microenvironment-mediated resistance while sparing normal stromal cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. V. Kurtova, K. Balakrishnan, R. Chen, W. Ding, S. Schnabl, M. P. Quiroga, M. Sivina, W. G. Wierda, Z. Estrov, M. J. Keating, et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance Blood, November 12, 2009; 114(20): 4441 - 4450. [Abstract] [Full Text] [PDF] J. A. Burger and V. Gandhi The lymphatic tissue microenvironments in chronic lymphocytic leukemia: in vitro models and the significance of CD40-CD154 interactions Blood, September 17, 2009; 114(12): 2560 - 2561. [Full Text] [PDF] R. Chen, W. G. Wierda, S. Chubb, R. E. Hawtin, J. A. Fox, M. J. Keating, V. Gandhi, and W. Plunkett Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia Blood, May 7, 2009; 113(19): 4637 - 4645. [Abstract] [Full Text] [PDF] J. Gordon Dis-Abl-ing CD40 buys toxic assets Blood, December 15, 2008; 112(13): 4787 - 4788. [Full Text] [PDF]

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