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AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death

Cell Death & Differentiation volume 31, pages 405–416 (2024)Cite this article

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Abstract

BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLXL inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors. Cell fractionation and phosphoproteomic analyses suggest that sensitization by dorsomorphin involves dephosphorylation of the proapoptotic BCL2 family member BAD at Ser75 and Ser99, leading BAD to translocate to mitochondria and inhibit BCLXL. Consistent with these results, BAD knockout or mutation to BAD S75E/S99E abolishes the sensitizing effects of dorsomorphin. Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.

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Fig. 1: Dorsomorphin or BAY-3827 inhibits BH3 mimetic-induced AMPK activation in ALL or AML cell lines.
Fig. 2: Dorsomorphin or BAY-3827 promotes BH3 mimetic-induced cell death in Jurkat and U937 cells.
Fig. 3: Dorsomorphin sensitizes clinical acute leukemic isolates to navitoclax or S63845.
Fig. 4: Dorsomorphin sensitizes to navitoclax/S63845-induced cell death through the mitochondrial pathway but does not alter BCL2 protein expression.
Fig. 5: BAD is essential for dorsomorphin-induced sensitization to navitoclax- or S63845-induced cell death in Jurkat cells.
Fig. 6: Dorsomorphin induces BAD phosphorylation at Ser75 and Ser99, which is important for dorsomorphin sensitization.
Fig. 7: Dorsomorphin plus navitoclax or S63845 inhibits xenograft growth in vivo.

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Data availability

This study includes no data deposited in external repositories. All the raw data and material reported in this paper will be shared by the lead contact upon request.

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Acknowledgements

We also acknowledge the assistance of the Mayo Clinic Proteomics Core, which is a shared resource of the Mayo Clinic Cancer Center (P30 CA15083).

Funding

This work is supported by the National Natural Science Foundation of China (No. 31970701 and No. 32100607), the Anhui Provincial Key R&D Program (No. 202104a07020007), and the co-operative grants from Anhui Medical University and Center of Medical Physics and Technology (Nos. LHJJ202006, LHJJ202007). Leukemia samples were collected with support of R01 CA225996, P30 CA015083 and P30 CA006973.

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Author notes

  1. These authors contributed equally: Jia Jia, Wenbo Ji.

Authors and Affiliations

  1. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China

    Jia Jia, Wenbo Ji, Kaiqin Ye, Lei Hu, Qingmei Deng, Hongzhi Wang & Haiming Dai

  2. University of Science and Technology of China, Hefei, 230026, China

    Jia Jia, Wenbo Ji & Lei Hu

  3. Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China

    Jia Jia, Wenbo Ji, Kaiqin Ye, Lei Hu, Qingmei Deng, Hongzhi Wang & Haiming Dai

  4. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, 55905, USA

    Antoine N. Saliba, Clifford M. Csizmar, Mrinal M. Patnaik & Scott H. Kaufmann

  5. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA

    Clifford M. Csizmar, X. Wei Meng, Annapoorna Venkatachalam, Xinyan Wu, Akhilesh Pandey & Scott H. Kaufmann

  6. Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA

    Kevin L. Peterson, Paula A. Schneider, X. Wei Meng, Annapoorna Venkatachalam, Karen S. Flatten, Scott H. Kaufmann & Haiming Dai

  7. Adult Leukemia Program, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, 21287, USA

    Jonathan A. Webster, B. Douglas Smith & Gabriel Ghiaur

  8. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA

    Xinyan Wu, Jun Zhong & Akhilesh Pandey

  9. Manipal Academy of Higher Education, Manipal, 576104, Kamataka, India

    Akhilesh Pandey

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  1. Jia Jia
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Contributions

Conceptualization: HD and SHK; Investigation: JJ, WJ, ANS, CMC, KY, LH, KLP, PAS, XWM, AV, XW, JZ, KSF, AP, HW, QD and HD; Clinical samples: ANS, MP, JAW, BDS, and GG; Writing: HD and SHK. The manuscript has been reviewed by all the authors.

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Correspondence to Scott H. Kaufmann or Haiming Dai.

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Jia, J., Ji, W., Saliba, A.N. et al. AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death. Cell Death Differ 31, 405–416 (2024). https://doi.org/10.1038/s41418-024-01283-9

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