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What does BCL-2 do? From new molecular insights to the clinical implications

Cell Death & Differentiation volume 33, pages 673–693 (2026) Cite this article

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Abstract

It took decades from the discovery of BCL-2, initially identified in chromosomal translocations associated with lymphoid malignancies, to understand how BCL-2 and its family members regulate apoptosis, launching a transformative journey in cancer biology often called “the road to ruin”. Developing powerful BCL-2 inhibitors for clinical use required decades. Yet, this remains as one of the most successful achievements in a field that started ~40 years ago, as recounted by its pioneers. BCL-2 was later found to inhibit apoptosis by preventing mitochondrial outer membrane permeabilization (MOMP), a breakthrough that clarified its role in cancer pathogenesis. Such effects of BCL-2 on MOMP prevent cytochrome c release and caspase activation, while its family members—anti-apoptotic proteins (e.g. BCL-2, BCL-XL) and pro-apoptotic proteins (e.g. BAX, BAK, BH3-only proteins)—orchestrate a delicate balance in cell death regulation. MicroRNAs like miR-15/16, often deleted in chronic lymphocytic leukaemia (CLL), modulate BCL-2 expression, driving oncogenesis. Mechanistically, BAX/BAK oligomerization forms mitochondrial pores, with sublethal MOMP triggering inflammation via cGAS-STING and NF-κB pathways. Alternative MOMP inducers (e.g. BOK) and mitochondrial dynamics further refine apoptotic control. Clinically, the BCL-2 inhibitor venetoclax has revolutionized CLL and acute myeloid leukemia (AML) treatment, showing efficacy in TP53-mutant CLL and elderly AML patients when combined with CD20 antibodies or hypomethylating agents. However, resistance, driven by BCL-2 mutations (e.g. Gly101Val) or MCL-1 upregulation, poses challenges. Limited success in solid tumors underscores the complexity of BCL-2 family dependencies. Future directions include novel inhibitors targeting MCL-1 or BCL-XL, BH3 profiling for precision therapy, and combinations with immune or DNA repair modulators. Non-apoptotic roles of BCL-2 in metabolism also warrant exploration. This review highlights the clinical success of BCL-2 inhibitors, addresses resistance mechanisms, and explores future directions, including sublethal MOMP, inflammatory outcomes, and novel inhibitors. Celebrating the collaborative, interdisciplinary efforts that transformed fundamental discoveries into life-saving therapies, this account underscores both the triumphs and the “potholes” encountered on the path to understanding apoptosis, while identifying open questions for ongoing research.

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Fig. 1: Dynamic regulation processes once activated in the outer mitochondrial membrane.
The alternative text for this image may have been generated using AI.
Fig. 2: BCL-2 ultimately engages the mitochondrial outer membrane permeabilization.
The alternative text for this image may have been generated using AI.
Fig. 3: The CLL translocation breakpoint.
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Fig. 4: The expression of miR-15a/15b/16 in patients with MDS and AML.
The alternative text for this image may have been generated using AI.
Fig. 5: Removal of BCL-2 induces remission of leukemia and improves survival.
The alternative text for this image may have been generated using AI.
Fig. 6: BH3 profiling.
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Fig. 7: CT scan of a patients, before and after Venetoclax.
The alternative text for this image may have been generated using AI.
Fig. 8: A personal timeline of apoptosis and BCL2.
The alternative text for this image may have been generated using AI.
Fig. 9: Timeline of the discovery of BCL2.
The alternative text for this image may have been generated using AI.

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Funding

Research in our labs is supported by the Max Planck Society, the European Research council (ERC), CoG 817758 (APOSITE) and AdG 787171 (POLICE), the Deutsche Forschungsgemeinschaft (CRC1403, CRC1218, TRR353), and the Austrian Science Fund (FWF), projects P36658, I5311, FG25, and I6642 (TRR353). This work has been supported by the European Union Next-Generation-EU via MUR-PNRR M4C2-II.3 PE6 project PE00000019 Heal Italia (CUP: E83C22004670001) to GM, AM, MS, GS; Associazione Italiana per la Ricerca contro il Cancro (AIRC) to GM (IG 2022 ID 27366; 2023-2027), Ministry of Health - HUB LIFE SCIENCE – Advanced Diagnostic- Italian network of excellence for advanced diagnosis (INNOVA) (PNC-E3-2022-23683266) to GM. The study was also supported by grants from the National Key R&D Program of China (2021YFA1100600 and 2022YFA0807300), the National Natural Science Foundation of China (32150710523, 81930085 and 82202032), Suzhou Foreign Academician Workstation Fund (SWY202202), Suzhou Science and Technology Bureau Fund (SYS2020087, ZXL2021440).

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Authors and Affiliations

  1. Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    Carlo M. Croce

  2. Cancer Research UK Scotland Institute, Glasgow, UK

    Stephen W. G. Tait

  3. School of Cancer Sciences, University of Glasgow, Glasgow, UK

    Stephen W. G. Tait

  4. Max Planck Institute of Biophysics, Frankfurt am Main, Germany

    Ana J. Garcia-Sáez

  5. Institute of Genetics, CECAD, University of Cologne, Cologne, Germany

    Ana J. Garcia-Sáez

  6. Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria

    Andreas Villunger

  7. CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Andreas Villunger

  8. Dana-Farber Cancer Institute, Harvard University, Cambridge, MA, USA

    Anthony Letai

  9. The Ernest and Helen Scott Haematological Research Institute, Department of Genetics, Genomics and Cancer Sciences, University of Leicester, Leicester, UK

    Harriet S. Walter & Martin J. S. Dyer

  10. Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Douglas R. Green

  11. The Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College Soochow University, Suzhou, China

    Yufang Shi

  12. Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy

    Gerry Melino

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  1. Carlo M. Croce
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  2. Stephen W. G. Tait
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Contributions

CMC and GM conceived the project, designed the structure of the manuscript. Each section has been designed, led and wrote by the distinct co-authors, as indicated. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Carlo M. Croce, Stephen W. G. Tait, Ana J. Garcia-Sáez, Andreas Villunger, Anthony Letai, Harriet S. Walter, Martin J. S. Dyer, Douglas R. Green, Yufang Shi or Gerry Melino.

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Competing interests

AV, DRG, YS, GM are editors in Cell Death Differentiation. GM reports honoraria from Fondazione Human Technopole and from Indivumed GmbH. MJSD reports research funding from BeiGene, Gilead, Loxo, AstraZeneca, and Roche pharmaceuticals and funding from BeiGene for meeting attendance. HSW reports honoraria from BeiGene for advisory board attendance.

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Croce, C.M., Tait, S.W.G., Garcia-Sáez, A.J. et al. What does BCL-2 do? From new molecular insights to the clinical implications. Cell Death Differ 33, 673–693 (2026). https://doi.org/10.1038/s41418-025-01607-3

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