Abstract
The inositol phosphatases phosphatase and tensin homologue (PTEN) and Src homology 2 domain-containing inositol phosphatase (SHIP) negatively regulate phosphatidylinositol-3-kinase (PI3K)-mediated growth, survival, and proliferation of hematopoietic cells. Although deletion of PTEN in mouse T cells results in lethal T cell lymphomas, we find that animals lacking PTEN or SHIP in B cells show no evidence of malignancy. However, concomitant deletion of PTEN and SHIP (bPTEN/SHIP(-/-)) results in spontaneous and lethal mature B cell neoplasms consistent with marginal zone lymphoma or, less frequently, follicular or centroblastic lymphoma. bPTEN/SHIP(-/-) B cells exhibit enhanced survival and express more MCL1 and less Bim. These cells also express low amounts of p27(kip1) and high amounts of cyclin D3 and thus appear poised to undergo proliferative expansion. Unlike normal B cells, bPTEN/SHIP(-/-) B cells proliferate to the prosurvival factor B cell activating factor (BAFF). Interestingly, although BAFF availability may promote lymphoma progression, we demonstrate that BAFF is not required for the expansion of transferred bPTEN/SHIP(-/-) B cells. This study reveals that PTEN and SHIP act cooperatively to suppress B cell lymphoma and provides the first direct evidence that SHIP is a tumor suppressor. As such, assessment of both PTEN and SHIP function are relevant to understanding the etiology of human B cell malignancies that exhibit augmented activation of the PI3K pathway.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / immunology
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Apoptosis Regulatory Proteins / metabolism
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B-Cell Activating Factor / genetics
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B-Cell Activating Factor / immunology
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B-Cell Activating Factor / metabolism
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B-Lymphocytes / enzymology
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B-Lymphocytes / immunology
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Bcl-2-Like Protein 11
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Cell Proliferation
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Cell Survival
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Cyclin D3 / genetics
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Cyclin D3 / immunology
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Cyclin D3 / metabolism
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / immunology
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Gene Deletion
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Gene Expression Regulation, Enzymologic*
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Gene Expression Regulation, Neoplastic*
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Humans
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Inositol Polyphosphate 5-Phosphatases
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Lymphoma, B-Cell / enzymology*
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / immunology
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Myeloid Cell Leukemia Sequence 1 Protein
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / immunology
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PTEN Phosphohydrolase / metabolism*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / immunology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / immunology
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Phosphoric Monoester Hydrolases / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / immunology
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / immunology
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Proto-Oncogene Proteins c-bcl-2 / metabolism
Substances
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Apoptosis Regulatory Proteins
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B-Cell Activating Factor
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Ccnd3 protein, mouse
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Cdkn1b protein, mouse
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Cyclin D3
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Mcl1 protein, mouse
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Membrane Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tnfsf13b protein, mouse
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Cyclin-Dependent Kinase Inhibitor p27
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Phosphoric Monoester Hydrolases
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Inositol Polyphosphate 5-Phosphatases
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PTEN Phosphohydrolase
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Pten protein, mouse