Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of pro-survival Bcl-2 with ABT-199.
Details
Publication Year 2014-01-09, Volume 28, Issue #6, Page 1207-15
Journal Title
Leukemia
Publication Type
Journal Article
Abstract
Overexpression of the pro-survival protein Bcl-2 marks many B lymphoid malignancies and contributes to resistance to many commonly used chemotherapeutic agents. The first effective BH3 mimetic inhibitors of Bcl-2, ABT-737 and navitoclax, also target Bcl-xL causing dose-limiting thrombocytopenia. This prompted the development of the Bcl-2 selective antagonist, ABT-199. Here, we show that in lymphoid cells, ABT-199 specifically causes Bax/Bak-mediated apoptosis that is triggered principally by the initiator BH3-only protein Bim. As expected, malignant cells isolated from patients with chronic lymphocytic leukaemia (CLL) are highly sensitive to ABT-199. However, we found that normal, untransformed mature B cells are also highly sensitive to ABT-199, both in vitro and in vivo. By contrast, the B cell precursors are largely spared, as are cells of myeloid origin. These results pinpoint the likely impact of the pharmacological inhibition of Bcl-2 by ABT-199 on the normal mature haemopoietic cell lineages in patients and have implications for monitoring during ABT-199 therapy, as well as for the clinical utility of this very promising targeted agent.Leukemia accepted article preview online, 9 January 2014. doi:10.1038/leu.2014.1.
Publisher
NATURE PUBLISHING GROUP
Keywords
ABT-199; ABT-737; BCL2; chronic lymphocytic leukaemia; apoptosis; lymphocyte subsets
WEHI Research Division(s)
Cancer And Haematology; Molecular Genetics Of Cancer; Chemical Biology
Rights Notice
© 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Creation Date: 2014-01-16 04:26:28
Last Modified: 2014-11-27 11:57:34
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