Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting
4 affiliations
- 1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- 2Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- 3Immunology Graduate Program, University of Cincinnati, Cincinnati, USA
- 4Department of Oncology and Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA. [email protected]
Abstract
The BCL-2 protein family controls the intrinsic apoptotic pathway through a delicate balance of pro- and anti-apoptotic members acting at the mitochondrial outer membrane. Anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, BCL-W, and BCL2A1 (BFL-1) function as critical survival factors whose dysregulation contributes to cancer development and therapeutic resistance. This review systematically examines the multilayered regulatory mechanisms governing these proteins, including transcriptional control by NF-κB, STAT3/5, and HIF-1α; post-transcriptional regulation through alternative splicing and microRNAs; and post-translational modifications that determine protein stability and function. The clinical success of venetoclax, a selective BCL-2 inhibitor, has established BCL-2 family targeting as an effective therapeutic strategy and fundamentally changed the management of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, therapeutic challenges persist: resistance emerges through MCL-1 upregulation, BCL-2 mutations, and metabolic reprogramming; BCL-XL inhibition causes dose-limiting thrombocytopenia; and MCL-1 inhibitors face class-wide cardiac toxicity. Emerging strategies to overcome these limitations include tissue-selective proteolysis-targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs) enabling tumor-targeted delivery, next-generation inhibitors that overcome resistance mutations, and biomarker-guided patient selection. This review provides an integrated overview of the regulatory mechanisms and evolving therapeutic strategies targeting anti-apoptotic BCL-2 family proteins, outlining both prominent successes and unresolved challenges.
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BibTeX
@article{wang2026antiapoptotic,
title = {{Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting}},
author = {Zhe Wang and Mutian Tang and Marina Konopleva},
journal = {Oncogenesis},
year = {2026},
month = jun,
doi = {10.1038/s41389-026-00632-2},
url = {https://doi.org/10.1038/s41389-026-00632-2},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting
AU - Zhe Wang
AU - Mutian Tang
AU - Marina Konopleva
PY - 2026
DA - 2026/06/03
JO - Oncogenesis
DO - 10.1038/s41389-026-00632-2
UR - https://doi.org/10.1038/s41389-026-00632-2
AB - The BCL-2 protein family controls the intrinsic apoptotic pathway through a delicate balance of pro- and anti-apoptotic members acting at the mitochondrial outer membrane. Anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, BCL-W, and BCL2A1 (BFL-1) function as critical survival factors whose dysregulation contributes to cancer development and therapeutic resistance. This review systematically examines the multilayered regulatory mechanisms governing these proteins, including transcriptional control by NF-κB, STAT3/5, and HIF-1α; post-transcriptional regulation through alternative splicing and microRNAs; and post-translational modifications that determine protein stability and function. The clinical success of venetoclax, a selective BCL-2 inhibitor, has established BCL-2 family targeting as an effective therapeutic strategy and fundamentally changed the management of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, therapeutic challenges persist: resistance emerges through MCL-1 upregulation, BCL-2 mutations, and metabolic reprogramming; BCL-XL inhibition causes dose-limiting thrombocytopenia; and MCL-1 inhibitors face class-wide cardiac toxicity. Emerging strategies to overcome these limitations include tissue-selective proteolysis-targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs) enabling tumor-targeted delivery, next-generation inhibitors that overcome resistance mutations, and biomarker-guided patient selection. This review provides an integrated overview of the regulatory mechanisms and evolving therapeutic strategies targeting anti-apoptotic BCL-2 family proteins, outlining both prominent successes and unresolved challenges.
SN - 2157-9024
ER -