PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis

Kallesh D. Jayappa; Brian Tran; Vicki L. Gordon; Christopher G. Morris; Shekhar Saha; Caroline C. Farrington; Caitlin M. O’Connor; Kaitin P. Zawacki; Krista M. Isaac; Mark Kester; Timothy P. Bender; Michael E. Williams; Craig A. Portell; Michael J. Weber; Goutham Narla

doi:10.1172/JCI155938

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Jayappa, K. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Tran, B. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Gordon, V. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Morris, C. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Saha, S. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Farrington, C. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by O’Connor, C. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Zawacki, K. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Isaac, K. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Kester, M. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Bender, T. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Williams, M. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Portell, C. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Weber, M. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States of America

²Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

³Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States of America

⁴Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, United States of America

⁵Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Narla, G. in: JCI | PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI155938.
Copyright © 2023, Jayappa et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published May 11, 2023 - Version history

Targeted therapies such as venetoclax (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple anti-apoptotic proteins and display resistance to pro-apoptotic agents. Here, we demonstrated that multidrug resistant CLL cells in vivo exhibit apoptosis restriction at a premitochondrial level due to insufficient activation of the Bax and Bak proteins. Co-immunoprecipitation analyses with selective BH-domain antagonists revealed that the pleotropic pro-apoptotic protein (Bim) is prevented from activating Bax/Bak by “switching” interactions to other upregulated anti-apoptotic proteins (Mcl-1/Bcl-xL/Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein Phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that a small molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug resistant leukemia/lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug resistant CLL cells through induction of mitochondrial permeability transition pores (mPTP), independent of Bax/Bak. DT-061 inhibited the growth of wild type and Bax/Bak double knockout multidrug resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug resistant CLL cells in patients, and validated a pharmacologically tractable pathway to deplete this reservoir.

Version 1 (May 11, 2023): In-Press Preview

PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis

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PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis

Kallesh D. Jayappa,1 Brian Tran,2 Vicki L. Gordon,1 Christopher G. Morris,1 Shekhar Saha,3 Caroline C. Farrington,2 Caitlin M. O’Connor,2 Kaitin P. Zawacki,2 Krista M. Isaac,4 Mark Kester,5 Timothy P. Bender,1 Michael E. Williams,4 Craig A. Portell,4 Michael J. Weber,1 and Goutham Narla2

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