ArticleThe Journal of clinical investigation2023
PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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The trial behind it
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Who cites it
9 citing papers in PubMed, 15 citations in OpenAlex.
- The protein phosphatase 2A-B56α complex regulates N-Myc degradation in neuroblastoma.The Journal of biological chemistry · 2026Article
- Reliable high-PAP-1-loaded polymeric micelles for cancer therapy: preparation, characterization, and evaluation of anti-tumor efficacy.Drug delivery · 2025Article
- Synergistic Efficacy of Chidamide and LB100 in Sézary Syndrome via TNC Downregulation and PI3K/AKT/mTOR Dephosphorylation.Cancer science · 2025Article
- PP2A Attenuates Thoracic Aneurysm and Dissection in Mouse Models of Marfan Syndrome.Hypertension (Dallas, Tex. : 1979) · 2025Article
- Protein serine/threonine phosphatases in tumor microenvironment: a vital player and a promising therapeutic target.Theranostics · 2025Review
- Mitochondrial involvement in PC: improving therapeutic strategies.Frontiers in pharmacology · 2025Review
- Diapause-like Drug-Tolerant Persister State: The Key to Nirvana Rebirth.Medicina (Kaunas, Lithuania) · 2024Review
- Altering phosphorylation in cancer through PP2A modifiers.Cancer cell international · 2024Review
- Targeting the PRMT1-cGAS-STING signaling pathway to enhance the anti-tumor therapeutic efficacy.Journal of cancer biology · 2024Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
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. 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.
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Registered trials
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