The application of BH3 mimetics in myeloid leukemias

Parry, N., Wheadon, H. and Copland, M. (2021) The application of BH3 mimetics in myeloid leukemias. Cell Death and Disease, 12, 222. (doi: 10.1038/s41419-021-03500-6) (PMID:33637708) (PMCID:PMC7908010)

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Abstract

Execution of the intrinsic apoptotic pathway is controlled by the BCL-2 proteins at the level of the mitochondrial outer membrane (MOM). This family of proteins consists of prosurvival (e.g., BCL-2, MCL-1) and proapoptotic (e.g., BIM, BAD, HRK) members, the functional balance of which dictates the activation of BAX and BAK. Once activated, BAX/BAK form pores in the MOM, resulting in cytochrome c release from the mitochondrial intermembrane space, leading to apoptosome formation, caspase activation, and cleavage of intracellular targets. This pathway is induced by cellular stress including DNA damage, cytokine and growth factor withdrawal, and chemotherapy/drug treatment. A well-documented defense of leukemia cells is to shift the balance of the BCL-2 family in favor of the prosurvival proteins to protect against such intra- and extracellular stimuli. Small molecule inhibitors targeting the prosurvival proteins, named ‘BH3 mimetics’, have come to the fore in recent years to treat hematological malignancies, both as single agents and in combination with standard-of-care therapies. The most significant example of these is the BCL-2-specific inhibitor venetoclax, given in combination with standard-of-care therapies with great success in AML in clinical trials. As the number and variety of available BH3 mimetics increases, and investigations into applying these novel inhibitors to treat myeloid leukemias continue apace the need to evaluate where we currently stand in this rapidly expanding field is clear.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Parry, Narissa and Copland, Professor Mhairi and Wheadon, Professor Helen
Authors: Parry, N., Wheadon, H., and Copland, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Death and Disease
Publisher:Springer Nature
ISSN:2041-4889
ISSN (Online):2041-4889
Published Online:26 February 2021
Copyright Holders:Copyright © The Author(s) 2021
First Published:First published in Cell Death and Disease 12:222
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173707Institutional Strategic Support Fund (2016)Anna DominiczakWellcome Trust (WELLCOTR)204820/Z/16/ZInstitute of Cardiovascular & Medical Sciences