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Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia
Open accessAbstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug's antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential.
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“PPZ exploited in this study is approved for clinical use as an anti-psychotic”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Gutierrez et al., 2014
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“a combination of metformin with perphenazine (PPZ), a US Food and Drug Administration-approved anti-psychotic drug that has been shown to modulate PP2A (Gutierrez et al., 2014), diminished the levels of phosphorylated GSK3 b and total MCL-1 (Figure S5B).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Gutierrez et al., 2014
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Self-citation
Metadata
- Authors
- Gutierrez, A., Pan, L., Groen, R. W. J., Baleydier, F., Kentsis, A., Marineau, J., Grebliunaite, R., Kozakewich, E., Reed, C., Pflumio, F., Poglio, S., Uzan, B., Clemons, P., VerPlank, L., An, F., Burbank, J., Norton, S., Tolliday, N., Steen, H., Weng, A. P., Yuan, H., Bradner, J. E., Mitsiades, C., Look, A. T., & Aster, J. C.
- Affiliations
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- Université Paris-Sud (FR)
- Broad Institute (US)
- BC Cancer Agency (CA)
- Corresponding author
- Aster, Jon C.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-01-09
- Volume
- 124
- Issue
- 2
- Pages
- 644-655
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3904599
- OpenAlex
- W2128575549
- Cited by
- 220
- References
- 73
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 12 · 2023: 13 · 2022: 19 · 2021: 14 · 2020: 27 · 2019: 26 · 2018: 22 · 2017: 14 · 2016: 30 · 2015: 16 · 2014: 10
- FWCI
- 23.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- European Commission (302428)
- National Institutes of Health (n01co12400-79-0-22)
- National Cancer Institute (N01CO12400, R01CA176746, N01-CO-012400, K08CA133103, P01CA109901)
- Topics
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Keywords
- T-cell acute lymphoblastic leukemia, phenothiazines, perphenazine, protein phosphatase 2A, apoptosis, antipsychotic drugs, drug repurposing, MYC overexpression, NOTCH1 mutation, Notch inhibitors, anticancer drug discovery
- MeSH terms
- Animals, Cell Survival, Chromatography, Affinity, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Perphenazine, Phenothiazines, Phosphorylation, Pigmentation, Mass Spectrometry, Time Factors, Zebrafish, Apoptosis, Dopamine Antagonists, Animals, Genetically Modified, Proteomics, Cell Line, Tumor, Mice, Receptors, Notch, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Protein Phosphatase 2
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