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Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice
Xiaohe Liu, … , Craig H. Bassing, Laurence A. Turka
Xiaohe Liu, … , Craig H. Bassing, Laurence A. Turka
Published June 1, 2010
Citation Information: J Clin Invest. 2010;120(7):2497-2507. https://doi.org/10.1172/JCI42382.
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Research Article Immunology Article has an altmetric score of 3

Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice

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Abstract

Mutations in the tumor-suppressor gene phosphatase and tensin homolog deleted on chromosome 10 (Pten) are associated with multiple cancers in humans, including T cell malignancies. Targeted deletion of Pten in T cells induces both a disseminated “mature phenotype” lymphoma and a lymphoproliferative autoimmune syndrome in mice. Here, we have shown that these two diseases are separable and mediated by T lineage cells of distinct developmental stages. Loss of PTEN was found to be a powerful driver of lymphomagenesis within the thymus characterized by overexpression of the c-myc oncogene. In an otherwise normal thymic environment, PTEN-deficient T cell lymphomas invariably harbored RAG-dependent reciprocal t(14:15) chromosomal translocations involving the T cell receptor alpha/delta locus and c-myc, and their survival and growth was TCR dependent, but Notch independent. However, lymphomas occurred even if TCR recombination was prevented, although these lymphomas were less mature, arose later in life, and, importantly, were dependent upon Notch pathways to upregulate c-myc expression. In contrast, using the complementary methods of early thymectomy and adoptive transfers, we found that PTEN-deficient mature T cells were unable to undergo malignant transformation but were sufficient for the development of autoimmunity. These data suggest multiple and distinct regulatory roles for PTEN in the molecular pathogenesis of lymphoma and autoimmunity.

Authors

Xiaohe Liu, Jodi L. Karnell, Bu Yin, Ruan Zhang, Jidong Zhang, Peiying Li, Yongwon Choi, Jonathan S. Maltzman, Warren S. Pear, Craig H. Bassing, Laurence A. Turka

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Figure 6

The development of autoimmunity in thymectomized PTEN-ΔT mice.

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The development of autoimmunity in thymectomized PTEN-ΔT mice.
(A) Repre...
(A) Representative splenic weights from thymectomized mice at 9.5–11 months of age. (B) WT and PTEN-ΔT mice that received a thymectomy were sacrificed at 9.5 months of age. Data represent lymphocyte profiles from the spleen of representative aged, thymectomized mice. (C) Elevated immunoglobulin levels from sera of 9.5-month-old thymectomized WT and PTEN-ΔT mice from B measured by ELISA. (D) Detection of serum dsDNA autoantibodies in 9.5-month-old thymectomized WT and PTEN-ΔT mice. Sera from the indicated mice was used to detect the presence of anti-dsDNA antibodies. Kinetoplast staining (as indicated by the arrow) indicates a positive antibody response to dsDNA. Original magnification, ×10. (E) Representative H&E staining of liver and lung of thymectomized WT and PTEN-ΔT mice at 9.5 months of age. All experiments described in A–E are representative of 4 mice of each group. (F) Defective AICD in PTEN-deficient CD4+ T cells. T cells were isolated from 3.5-week-old PTEN-ΔT and WT mice and cultured in the presence of α-CD3, α-CD28, and IL-2. Viable cells were fractionated and restimulated with α-CD3 for an additional 16 hours, and cell death was evaluated by flow cytometry with the indicated markers gated on CD4+ population. The data are representative of 2 independent experiments on T cells from a total of 6 mice of each genotype.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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