@article{a95044482a7240cb82fd1a81c25823c0,
title = "PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis",
abstract = "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. Coimmunoprecipitation 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 doubleknockout, 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.",
author = "Jayappa, {Kallesh D.} and Brian Tran and Gordon, {Vicki L.} and Christopher Morris and Shekhar Saha and Farrington, {Caroline C.} and O'Connor, {Caitlin M.} and Zawacki, {Kaitlin P.} and Isaac, {Krista M.} and Mark Kester and Bender, {Timothy P.} and Williams, {Michael E.} and Portell, {Craig A.} and Weber, {Michael J.} and Goutham Narla",
note = "Funding Information: This study was supported by the UVA Cancer Center (P30 NCI CA044579); the V Foundation for Cancer Research (T-2016-004 and DM2019-035); the UVA Lymphoma and Leukemia Research Fund; the NIH shared instrument fund (S10RR031633); and NIH research funding (R01-CA-181654 and R01-CA-240993). The study was also supported by a grant from the Lymphoma Research Foundation (to CAP as an LRF Scholar). Clinical trial NCT02419560 is supported by a grant to the UVA from AbbVie. We acknowledge the contributions of the UVA Cancer Center (support grant P30CA044579) and the UVA Oncology Research Information Exchange Network (ORIEN) Team and UVA BTRF with Partners in Discovery for Total Cancer Care at the UVA (protocol IRB HSR 18445) for the consenting, specimen procurement and processing, clinical data abstraction, and access to the clinical data. We thank Joanne Lannigan, D. Michael Solga, and other members of the UVA Flow Cytometry Core Facility and staff at the flow cytometry core facility in the Beirne B. Carter Center for Immunology Research for assistance with analytical flow cytometry. We are especially thankful to Timothy Bender and Todd Fox and their laboratory members for providing logistical support. This body of work is dedicated to Michael J. Weber, who died on February 11, 2021, and Mark Kester, who died on July 20, 2022. Funding Information: Authorship note: MJW and GN contributed equally to this work. Conflict of interest: CMO receives consulting fees from RAPPTA Therapeutics. CAP receives clinical trial research support from AbbVie and Merck, via the UVA Office of Sponsored Programs. CAP has received clinical trial research support from Genentech/ Roche, TG therapeutics, Infinity, BeiGene, SeaGen, Xencor, and Acerta/AstraZeneca. CAP has also consulted for Genentech, Bayer, BeiGene, Janssen, and Pharmacyclics. GN receives research support from RAPPTA Therapeutics and has an equity interest in and receives consulting fees from RAPPTA Therapeutics. GN acknowledges the support of the Rogel Cancer Center and is a Rogel Scholar. MEW has received clinical trial research support from Janssen, Pharmacyclics, and TG Therapeutics and consulting fees from Gilead Sciences, Abbvie, Astra-Zeneca, Celgene, Janssen, Verastem and TG Therapeutics. For MK, ceramide nanoliposomes have been licensed by Penn State Research Foundation to Keystone Nano Inc. (US patent 9028863). MK is chief technology officer (CTO) and co-founder of Keystone Nano. Copyright: {\textcopyright} 2023, Jayappa et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: October 26, 2021; Accepted: May 9, 2023; Published: July 3, 2023. Reference information: J Clin Invest. 2023;133(13):e155938. https://doi.org/10.1172/JCI155938. Publisher Copyright: {\textcopyright} 2023, Jayappa et al.",
year = "2023",
month = jul,
day = "3",
doi = "10.1172/JCI155938",
language = "English",
volume = "133",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "13",
}