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  • Review Article
  • Published:

Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia

Nature Reviews Clinical Oncology volume 22, pages 847–868 (2025)Cite this article

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Abstract

Acute myeloid leukaemia (AML) remains a challenging haematological malignancy, with most patients developing resistance to standard-of-care (SOC) treatments. This resistance is often attributed to the overexpression of anti-apoptotic BCL-2 family proteins, which regulate the intrinsic apoptotic pathway by inhibiting pro-apoptotic effector proteins such as BAX and BAK. AML cells exploit this imbalance to evade apoptosis and sustain survival, necessitating the development of novel therapeutic strategies. BH3 mimetics are small-molecule inhibitors targeting the pro-survival BCL-2 family proteins and have emerged as promising agents in patients with AML who are unable to receive high-intensity induction chemotherapy. Co-treatment with the BCL-2-specific inhibitor venetoclax and various SOC therapies has been proven effective, with several combinations now approved by the US Food and Drug Administration for adults with AML who are ≥75 years of age and/or are ineligible for intensive induction chemotherapy, on the basis of improved response rates and survival outcomes compared with the previous SOC. In this Review, we highlight the transformative potential of BH3 mimetics in AML therapy, including ongoing studies investigating novel combination regimens and efforts to further refine treatment strategies, with the ultimate goal of improving outcomes for patients with AML.

Key points

  • Resistance to standard treatments for acute myeloid leukaemia (AML) is often attributed to the overexpression of anti-apoptotic BCL-2 family proteins, which inhibit apoptosis and sustain cancer cell survival, posing a major therapeutic challenge.

  • BH3 mimetics, which target pro-survival BCL-2 proteins, have demonstrated substantial anticancer activity, effectively overcoming resistance in patients with AML and improving therapeutic outcomes, especially when combined with hypomethylating agents or low-dose cytarabine.

  • Venetoclax, a potent BCL-2-specific BH3 mimetic, has revolutionized the management of patients with AML owing to improved efficacy when combined with standard therapies, leading to US Food and Drug Administration approval of this agent for specific groups of patients with AML.

  • Innovative sequential or combinatorial approaches targeting BCL-xL and MCL-1 dependencies will be crucial to addressing the current challenges, including thrombocytopenia and the limited ability to target resistant BCL-2 family proteins.

  • Techniques such as BH3 profiling, mitochondrial profiling and gene and/or protein expression profiling are transforming the management of patients with AML by enabling precise, personalized therapies and enhancing the optimization of therapeutic regimens, leading to improved patient outcomes.

  • The future treatment of patients with AML lies in developing novel drug combinations, optimizing BH3 mimetic dosages, mitigating adverse effects and exploring dual-action therapies.

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Fig. 1: The extrinsic and intrinsic apoptotic pathways.
Fig. 2: BAX/BAK activation.
Fig. 3: Mechanisms of venetoclax-induced apoptosis.
Fig. 4: Timeline of the development of venetoclax.
Fig. 5: Mechanisms of resistance to venetoclax in AML.
Fig. 6: Role of other anti-apoptotic BCL-2 proteins in resistance to venetoclax.
Fig. 7: The role of genomic instability in the development of resistance to venetoclax.

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Change history

  • 11 September 2025

    In the version of the article initially published, the initials “S.D.B., P.D., M.K.” were inadvertently omitted from the Author contributions section and have now been added. Additionally, the initials “C.D.N.” have now been amended to “C.D.D.”. These corrections have been made to the HTML and PDF versions of the article.

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Acknowledgements

The work of A.P.K. was supported by the NUHS Seed Grant, National University of Singapore (NUHSRO/2023/039/RO5+6/Seed-Mar/04). The work of C.G. is supported by NIH grant 4R00CA252602-04, a V Foundation award V2023-008 and a New Jersey Health Foundation grant PC 99-24.

Author information

Authors and Affiliations

  1. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy

    Antonino Glaviano & Patrizia Diana

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Ellen Weisberg & James D. Griffin

  3. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Ellen Weisberg & James D. Griffin

  4. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Hiu Y. Lam, Donavan J. J. Tan & Alan P. Kumar

  5. NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Hiu Y. Lam, Donavan J. J. Tan & Alan P. Kumar

  6. School of Chemical and Life Sciences, Singapore Polytechnic, Singapore Polytechnic, Singapore, Singapore

    Donavan J. J. Tan

  7. Centre for Haematology, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK

    Andrew J. Innes

  8. Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK

    Andrew J. Innes

  9. Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    Yubin Ge

  10. Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Catherine E. Lai

  11. Department of Hematology and Oncology, Medical Center, University of Chicago, Chicago, IL, USA

    Wendy Stock

  12. Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

    Christina Glytsou

  13. Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers University, The State University of New Jersey, New Brunswick, NJ, USA

    Christina Glytsou

  14. Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, VU Medical Center, Amsterdam, Netherlands

    Linda Smit

  15. Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Tatsushi Yoshida

  16. Department of Medicine, Division of Hematology, Stanford Cancer Institute, Stanford University, Stanford, CA, USA

    Tian Y. Zhang

  17. Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University, Stanford, CA, USA

    Vanessa E. Kennedy

  18. Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    B. Douglas Smith

  19. OPALE Carnot Institute, Gustave Roussy Cancer Campus, Université Paris-Saclay, Paris, France

    Thomas Mercher

  20. Department of Hematology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Paris, France

    Stéphane de Botton

  21. Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York City, NY, USA

    Marina Konopleva

  22. Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

    Michael J. Mauro

  23. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Courtney D. DiNardo

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  1. Antonino Glaviano
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  2. Ellen Weisberg
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Contributions

A.G., E.W., H.Y.L., D.J.J.T., M.J.M., J.D.G., C.D.D. and A.P.K. researched data for the manuscript, A.G., E.W., H.Y.L., D.J.J.T., A.J.I., Y.G., C.E.L., W.S., C.G., L.S., T.Y., T.Y.Z., V.E.K., B.D.S., T.M., S.D.B., P.D., M.K., M.J.M., J.D.G., C.D.D. and A.P.K. wrote the manuscript, and all authors made a significant contribution to discussions of content and edited and/or reviewed the manuscript before submission.

Corresponding authors

Correspondence to Courtney D. DiNardo or Alan P. Kumar.

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Competing interests

B.D.S. is a consultant and adviser of Servier. M.K. is a consultant of AbbVie, Adaptive, AmMax, Curis, Janssen, Kyowa Kirin, Menarini/Stemline Therapeutics, Novartis, Sanofi Aventis, Servier and Vincerx and is an adviser of AbbVie, Auxenion GmbH, Dark Blue Therapeutics, Legend, MEI Pharma, Menarini/Stemline Therapeutics, Novartis and Syndax and receives research funding from AbbVie, Janssen and Klondike Biopharma. C.D.D. is a consultant and/or adviser of Abbvie, Astellas, AstraZeneca, BMS, Daiichi Sankyo, GenMab, GSK, Rigel, Ryvu, Schrodinger, Servier and Solu Therapeutics and has received research funding from Abbvie, Astex, Beigene, BMS, Jazz, ImmuneOnc, Remix, Servier, Schrodinger and Systimmune. A.P.K. serves on the advisory board for AUM Biosciences. The other authors declare no competing interests.

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Glaviano, A., Weisberg, E., Lam, H.Y. et al. Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia. Nat Rev Clin Oncol 22, 847–868 (2025). https://doi.org/10.1038/s41571-025-01068-0

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