1. ¹Department of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
2. ²Department of Cell Biology and Histology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
3. ³Department of Immunology Discovery, Genentech Inc., South San Francisco, CA, USA

Correspondence: Professor H Spits, Department of Immunology Discovery, Genentech Inc., 1 DNA Way, Mail Stop 34, South San Francisco, CA 94080, USA. E-mail: spits.hergen@gene.com

Received 18 September 2007; Accepted 5 November 2007; Published online 29 November 2007.

Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (Pten) is a tumor suppressor protein whose loss of lipid phosphatase activity is associated with lymphomagenesis. We made use of the Cre-loxP system to delete Pten expression in Lck- or CD4-expressing T-lineage cells. Mice initially showed modest thymic hyperplasia and subsequently developed expanding and infiltrating T-cell lymphomas, leading to a premature death within 5 to 23 weeks. Frequently, all thymocyte and peripheral T-cell populations displayed phenotypes characteristic for immature developing thymocyte precursors and shared elevated levels of clonally rearranged T-cell receptor (TCR) chains. In concert, CD2, CD5, CD3 and CD44, proteins associated with increased expression and signaling capacity of both the immature pre-TCR and the mature TCR, were more abundantly expressed, reflecting a constitutive state of activation. Although most T-cell lymphomas had acquired the capability to infiltrate the periphery, not all populations left the thymus and expanded clonally exclusively in the thymus. In line with this, only transplantation of thymocytes with infiltrating capacity gave rise to T-cell lymphoma in immunodeficient recipients. These results indicate that T-cell-specific Pten deletion during various stages of thymocyte development gives rise to clonally expanding T-cell lymphomas that frequently infiltrate the periphery, but originate in the thymus.