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Title: A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells
Authors: Vogler, Meike
Dinsdale, David
Sun, Xiao-Ming
Young, Kenneth W.
Butterworth, Michael
Nicotera, Pierluigi
Dyer, Martin J. S.
Cohen, Gerald M.
First Published: 29-Feb-2008
Publisher: The Nature Publishing Group
Citation: Cell Death and Differentiation, 2008, 15 (February), pp. 820-830
Abstract: Primary chronic lymphocytic leukemia (CLL) cells are exquisitely sensitive to ABT-737, a small molecule BCL2-antagonist, which induces many of the classical biochemical and ultrastructural features of apoptosis, including BAX/BAK oligomerization, cytochrome c release, caspase activation and chromatin condensation. Surprisingly, ABT-737 also induces mitochondrial inner membrane permeabilization (MIMP) resulting in mitochondrial matrix swelling and rupture of the outer mitochondrial membrane (OMM), so permitting the rapid efflux of cytochrome c from mitochondrial cristae and facilitating rapid caspase activation and apoptosis. BAX and BAK appear to be involved in the OMM discontinuities as they localize to the OMM breakpoints. Notably, ABT-737 induced mitochondrial matrix swelling and OMM discontinuities in other primary B-cell malignancies, including mantle cell, follicular and marginal zone lymphoma cells but not in several cell lines studied. Thus, we describe a new paradigm of apoptosis in primary B-cell malignancies, whereby targeting of BCL2 results in all the classical features of apoptosis together with OMM rupture independent of caspase activation. This mechanism may be far more prevalent than hitherto recognized due to the failure of most methods, used to measure apoptosis, to recognize such a mechanism.
DOI Link: 10.1038/cdd.2008.25
ISSN: 1350-9047
Type: Article
Rights: This is the author's final draft of the paper published as Cell Death and Differentiation, 2008, 15, pp. 820-830. The final version is available from Doi: 10.1038/cdd.2008.25
Appears in Collections:Published Articles, MRC Toxicology Unit

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