期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 2, 页码 644-655出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI65093
关键词
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资金
- NIH [1K08CA133103, 5P01CA109901]
- Leukemia and Lymphoma Society
- William Lawrence Blanche Hughes Foundation
- Bear Necessities Pediatric Cancer Foundation
- Ligue Nationale contre le Cancer
- Association Laurette Fugain
- Institut National du Cancer (INCA)
- Universites Paris Diderot and Paris Sud
- INSERM
- CEA and Canceropole Ile de France (StemPole)
- European Union [302428]
- NCI Initiative for Chemical Genetics [N01-CO-12400]
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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