PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis
Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here,...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2023-07-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI155938 |
| _version_ | 1797634428529278976 |
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| author | Kallesh D. Jayappa Brian Tran Vicki L. Gordon Christopher Morris Shekhar Saha Caroline C. Farrington Caitlin M. O’Connor Kaitlin P. Zawacki Krista M. Isaac Mark Kester Timothy P. Bender Michael E. Williams Craig A. Portell Michael J. Weber Goutham Narla |
| author_facet | Kallesh D. Jayappa Brian Tran Vicki L. Gordon Christopher Morris Shekhar Saha Caroline C. Farrington Caitlin M. O’Connor Kaitlin P. Zawacki Krista M. Isaac Mark Kester Timothy P. Bender Michael E. Williams Craig A. Portell Michael J. Weber Goutham Narla |
| author_sort | Kallesh D. Jayappa |
| collection | DOAJ |
| description | Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by “switching” interactions to other upregulated antiapoptotic 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 small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, 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. |
| first_indexed | 2024-03-11T12:08:43Z |
| format | Article |
| id | doaj.art-533a790882534037b799d173898330eb |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:08:43Z |
| publishDate | 2023-07-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-533a790882534037b799d173898330eb2023-11-07T16:20:34ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-07-0113313PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosisKallesh D. JayappaBrian TranVicki L. GordonChristopher MorrisShekhar SahaCaroline C. FarringtonCaitlin M. O’ConnorKaitlin P. ZawackiKrista M. IsaacMark KesterTimothy P. BenderMichael E. WilliamsCraig A. PortellMichael J. WeberGoutham NarlaTargeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by “switching” interactions to other upregulated antiapoptotic 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 small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, 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.https://doi.org/10.1172/JCI155938Cell biologyOncology |
| spellingShingle | Kallesh D. Jayappa Brian Tran Vicki L. Gordon Christopher Morris Shekhar Saha Caroline C. Farrington Caitlin M. O’Connor Kaitlin P. Zawacki Krista M. Isaac Mark Kester Timothy P. Bender Michael E. Williams Craig A. Portell Michael J. Weber Goutham Narla PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis The Journal of Clinical Investigation Cell biology Oncology |
| title | PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis |
| title_full | PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis |
| title_fullStr | PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis |
| title_full_unstemmed | PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis |
| title_short | PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis |
| title_sort | pp2a modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mptp dependent apoptosis |
| topic | Cell biology Oncology |
| url | https://doi.org/10.1172/JCI155938 |
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