Abstract
The genetic mechanisms responsible for increased incidence of lymphoma in immunocompromised individuals have not been fully elucidated. We show that, in a line of TCR transgenic TG-B mice, an insertional mutation in one allele of the Epm2a locus and epigenetic silencing of another led to a high rate of lymphoma with early onset. Overexpressing Epm2a suppressed the growth of established tumor cells and the development of lymphoma in the TG-B mice, while specific silencing of the locus increased tumorigenesis in the immune-deficient host. Downregulation of Epm2a expression is widespread among mouse and human lymphoma cell lines. Epm2a-encoded laforin is a phosphatase for GSK-3beta and an important repressor in the Wnt signaling pathway. Inactivation of Epm2a resulted in increased Wnt signaling and tumorigenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Base Sequence
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Cell Line
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DNA Methylation
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Dual-Specificity Phosphatases
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Gene Expression Regulation, Neoplastic
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Immunocompromised Host / immunology*
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Mice
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Mice, Transgenic
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Neoplasms / genetics
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Neoplasms / immunology
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Neoplasms / metabolism*
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Neoplasms / pathology*
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Protein Tyrosine Phosphatases, Non-Receptor
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Receptors, Antigen, T-Cell / genetics
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Signal Transduction*
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Survival Rate
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Wnt Proteins / metabolism*
Substances
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Receptors, Antigen, T-Cell
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Wnt Proteins
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Glycogen Synthase Kinase 3
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Dual-Specificity Phosphatases
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Epm2a protein, mouse
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Protein Tyrosine Phosphatases
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Protein Tyrosine Phosphatases, Non-Receptor
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EPM2A protein, human