Distinct roles for PTEN in prevention of T cell  lymphoma and autoimmunity in mice.
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.
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Xiaohe
X
Liu
Jodi L
JL
Karnell
Bu
B
Yin
Ruan
R
Zhang
Jidong
J
Zhang
Peiying
P
Li
Yongwon
Y
Choi
Jonathan S
JS
Maltzman
Warren S
WS
Pear
Craig H
CH
Bassing
Laurence A
LA
Turka
D000818:Animals; D056735:Autoimmune Lymphoproliferative Syndrome; D005796:Genes; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology; D014178:Translocation, Genetic
D016693:Receptors, Antigen, T-Cell, alpha-beta; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human