+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Mice lacking both PTEN and SHIP phosphatases develop spontaneous B cell lymphoma.


          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.

          Related collections

          Most cited references45

          • Record: found
          • Abstract: found
          • Article: not found

          Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis.

          The tumour-suppressor phosphatase with tensin homology (PTEN) is the most important negative regulator of the cell-survival signalling pathway initiated by phosphatidylinositol 3-kinase (PI3K). Although PTEN is mutated or deleted in many tumours, deregulation of the PI3K-PTEN network also occurs through other mechanisms. Crosstalk between the PI3K pathways and other tumorigenic signalling pathways, such as those that involve Ras, p53, TOR (target of rapamycin) or DJ1, can contribute to this deregulation. How does the PI3K pathway integrate signals from numerous sources, and how can this information be used in the rational design of cancer therapies?
            • Record: found
            • Abstract: found
            • Article: not found

            Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways.

            Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17-92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways.
              • Record: found
              • Abstract: found
              • Article: not found

              Inositol phosphatase SHIP1 is a primary target of miR-155.

              MicroRNA-155 (miR-155) has emerged as a critical regulator of immune cell development, function, and disease. However, the mechanistic basis for its impact on the hematopoietic system remains largely unresolved. Because miRNAs function by repressing specific mRNAs through direct 3'UTR interactions, we have searched for targets of miR-155 implicated in the regulation of hematopoiesis. In the present study, we identify Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1) as a direct target of miR-155, and, using gain and loss of function approaches, show that miR-155 represses SHIP1 through direct 3'UTR interactions that have been highly conserved throughout evolution. Repression of endogenous SHIP1 by miR-155 occurred following sustained over-expression of miR-155 in hematopoietic cells both in vitro and in vivo, and resulted in increased activation of the kinase Akt during the cellular response to LPS. Furthermore, SHIP1 was also repressed by physiologically regulated miR-155, which was observed in LPS-treated WT versus miR-155(-/-) primary macrophages. In mice, specific knockdown of SHIP1 in the hematopoietic system following retroviral delivery of a miR-155-formatted siRNA against SHIP1 resulted in a myeloproliferative disorder, with striking similarities to that observed in miR-155-expressing mice. Our study unveils a molecular link between miR-155 and SHIP1 and provides evidence that repression of SHIP1 is an important component of miR-155 biology.

                Author and article information

                J Exp Med
                J. Exp. Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                25 October 2010
                : 207
                : 11
                : 2407-2420
                [1 ]Program of Inflammatory Disease Research, Infectious and Inflammatory Disease Center, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037
                [2 ]Section of Molecular Biology, Division of Biological Sciences , and [3 ]University of California San Diego Cancer Center, University of California San Diego, La Jolla, CA 92093
                [4 ]Laboratory of Immunopathology and [5 ]Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
                [6 ]Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065
                Author notes
                CORRESPONDENCE Robert C. Rickert: robert@ 123456sanfordburnham.org

                A.V. Miletic, A.N. Anzelon-Mills, and D.M. Mills contributed equally to this paper.

                © 2010 Miletic et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).




                Comment on this article