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Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737
Victoria Del Gaizo Moore, … , Carl D. Novina, Anthony Letai
Victoria Del Gaizo Moore, … , Carl D. Novina, Anthony Letai
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):112-121. https://doi.org/10.1172/JCI28281.
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Research Article Oncology

Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737

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Abstract

Antiapoptotic B cell leukemia/lymphoma 2 (BCL2) family proteins are expressed in many cancers, but the circumstances under which these proteins are necessary for tumor maintenance are poorly understood. We exploited a novel functional assay that uses BCL2 homology domain 3 (BH3) peptides to predict dependence on antiapoptotic proteins, a strategy we call BH3 profiling. BH3 profiling accurately predicts sensitivity to BCL2 antagonist ABT-737 in primary chronic lymphocytic leukemia (CLL) cells. BH3 profiling also accurately distinguishes myeloid cell leukemia sequence 1 (MCL1) from BCL2 dependence in myeloma cell lines. We show that the special sensitivity of CLL cells to BCL2 antagonism arises from the requirement that BCL2 tonically sequester proapoptotic BIM in CLL. ABT-737 displaced BIM from BCL2’s BH3-binding pocket, allowing BIM to activate BAX, induce mitochondrial permeabilization, and rapidly commit the CLL cell to death. Our experiments demonstrate that BCL2 expression alone does not dictate sensitivity to ABT-737. Instead, BCL2 complexed to BIM is the critical target for ABT-737 in CLL. An important implication is that in cancer, BCL2 may not effectively buffer chemotherapy death signals if it is already sequestering proapoptotic BH3-only proteins. Indeed, activator BH3-only occupation of BCL2 may prime cancer cells for death, offering a potential explanation for the marked chemosensitivity of certain cancers that express abundant BCL2, such as CLL and follicular lymphoma.

Authors

Victoria Del Gaizo Moore, Jennifer R. Brown, Michael Certo, Tara M. Love, Carl D. Novina, Anthony Letai

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Figure 1

Schema of the intrinsic or mitochondrial programmed cell death pathway.

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Schema of the intrinsic or mitochondrial programmed cell death pathway.
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In response to death signaling, activator BH3-only proteins are triggered to interact with BAX and BAK, inducing BAX and BAK oligomerization. This oligomerization is followed by MOMP, which releases proapoptotic factors such as cytochrome c to the cytosol. Cytosolic cytochrome c forms a complex with apoptosis protease–activating factor–1 (APAF-1) and caspase-9 to make the holoenzyme known as the apoptosome, which in turn activates effector caspase-3, leading to widespread proteolysis. This pathway can be interrupted by antiapoptotic members, such as BCL2, which can bind activator BH3-only proteins, preventing their interaction with BAX and BAK. This inhibitory interaction can itself be antagonized by sensitizer BH3-only domains, which compete for the binding site in BCL2, displacing activators bound by BCL2. BFL1, BCL2-related gene expressed in fetal liver.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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