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|Title:||Concurrent upregulation of BCL-XL and BCL2A1 induces ~1000-fold resistance to ABT-737 in chronic lymphocytic leukemia.|
Walewska, Renata J.
Dyer, Martin J. S.
Cohen, Gerald M.
|Publisher:||The American Society of Hematology|
|Citation:||Blood, 2009, 113 (18), pp. 4403-4413.|
|Abstract:||ABT-737 and its orally active analog, ABT-263, are rationally designed inhibitors of BCL2 and BCL-XL. ABT-263 shows promising activity in early phase 1 clinical trials in B-cell malignancies, particularly chronic lymphocytic leukemia (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. Because 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 interleukin-4 (IL-4) to mimic the lymph node microenvironment. CLL cells thus cultured developed an approximately 1000-fold resistance to ABT-737 within 24 hours. 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 after 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.|
|Rights:||This paper was published as Blood, 2009, 113 (18), pp. 4403-4413. © 2009 by The American Society of Hematology. It is also available from http://bloodjournal.hematologylibrary.org/cgi/content/full/113/18/4403. It appears here with the permission of the American Society of Hematology. Doi: 10.1182/blood-2008-08-173310|
|Appears in Collections:||Published Articles, MRC Toxicology Unit|
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