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Blood, 30 April 2009, Vol. 113, No. 18, pp. 4403-4413.
Prepublished online as a Blood First Edition Paper on November 13, 2008; DOI 10.1182/blood-2008-08-173310.
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Submitted August 11, 2008
Accepted October 28, 2008
Concurrent upregulation of BCL-XL and BCL2A1 induces ~1000-fold resistance to ABT-737 in chronic lymphocytic leukemia
Meike Vogler, Michael Butterworth, Aneela Majid, Renata J Walewska, Xiao-Ming Sun, Martin JS Dyer, and Gerald M Cohen*
MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom
* Corresponding author; email: gmc2{at}le.ac.uk.
ABT-737 and its orally active analogue, ABT-263, are rationally designed inhibitors of BCL2 and BCL-XL. ABT-263 shows promising activity in early phase I clinical trials in B-cell malignancies, particularly chronic lymphocytic leukaemia (CLL). In vitro, peripheral blood CLL cells are extremely sensitive to ABT-737 (EC50 ~7 nM), with rapid induction of apoptosis in all 60 patients tested, independent of parameters associated with disease progression and chemotherapy resistance. In contrast to data from cell lines, ABT-737-induced apoptosis in CLL cells was largely MCL1-independent. Since CLL cells within lymph nodes are more resistant to apoptosis than those in peripheral blood, CLL cells were cultured on CD154-expressing fibroblasts in the presence of IL-4 to mimic the lymph node microenvironment. CLL cells thus cultured developed ~1,000-fold resistance to ABT-737 within 24 h. Investigations of the underlying mechanism revealed that this resistance occurred upstream of mitochondrial perturbation and involved de novo synthesis of the antiapoptotic proteins BCL-XL and BCL2A1, which were responsible for resistance to low and high ABT-737 concentrations, respectively. Our data indicate that following therapy with ABT-737-related inhibitors, resistant CLL cells might develop in lymph nodes in vivo and that treatment strategies targeting multiple BCL2 antiapoptotic members simultaneously may have synergistic activity.
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