Abstract
T-cell acute lymphoblastic leukemia (T-ALL) patients frequently display NOTCH1 activating mutations and Notch can transcriptionally down-regulate the tumor suppressor PTEN. However, it is not clear whether NOTCH1 mutations associate with decreased PTEN expression in primary T-ALL. Here, we compared patients with or without NOTCH1 mutations and report that the former presented higher MYC transcript levels and decreased PTEN mRNA expression. We recently showed that T-ALL cells frequently display CK2-mediated PTEN phosphorylation, resulting in PTEN protein stabilization and concomitant functional inactivation. Accordingly, the T-ALL samples analyzed, irrespectively of their NOTCH1 mutational status, expressed significantly higher PTEN protein levels than normal controls. To evaluate the integrated functional impact of Notch transcriptional and CK2 post-translational inactivation of PTEN, we treated T-ALL cells with both the gamma-secretase inhibitor DAPT and the CK2 inhibitors DRB/TBB. Our data suggest that combined use of gamma-secretase and CK2 inhibitors may have therapeutic potential in T-ALL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / metabolism
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Blotting, Western
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Casein Kinase II / antagonists & inhibitors*
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Casein Kinase II / metabolism*
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Cell Proliferation / drug effects
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Cell Size / drug effects
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Child
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Dichlororibofuranosylbenzimidazole / pharmacology
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Drug Therapy, Combination
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Leukemic
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Humans
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Mutation / genetics
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PTEN Phosphohydrolase / genetics*
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PTEN Phosphohydrolase / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor, Notch1 / genetics*
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Receptor, Notch1 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Triazoles / pharmacology
Substances
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4,5,6,7-tetrabromobenzotriazole
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Enzyme Inhibitors
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NOTCH1 protein, human
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RNA, Messenger
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Receptor, Notch1
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Triazoles
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Dichlororibofuranosylbenzimidazole
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Casein Kinase II
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PTEN Phosphohydrolase
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PTEN protein, human
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Amyloid Precursor Protein Secretases