Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases

Journal of Experimental Medicine - Tập 207 Số 11 - Trang 2407-2420 - 2010
Ana V. Miletic1, Amy Anzelon-Mills1, David Mills1, Sidne A. Omori1, Irene M. Pedersen2,3,4, Dong‐Mi Shin5,6, Jeffrey V. Ravetch7, Silvia Bolland5,6, Herbert C. Morse5,6, Robert C. Rickert1
1Program of Inflammatory Disease Research, Infectious and Inflammatory Disease Center, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037 1
2Section of Molecular Biology, Division of Biological Sciences 2 , and 3
3Section of Molecular Biology, Division of Biological Sciences, and University of California San Diego Cancer Center, University of California San Diego, La Jolla, CA 92093
4University of California San Diego Cancer Center, University of California San Diego, La Jolla, CA 92093 2 , and 3
5Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852 4 and 5
6Laboratory of Immunopathology and Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
7Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY, 10065.

Tóm tắt

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 p27kip1 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.

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Journal of Experimental Medicine

Tập 207 Số 11

2407-2420

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