The Nuclear Effector of Wnt-Signaling, Tcf1, Functions as a T-Cell–Specific Tumor Suppressor for Development of Lymphomas

Abstract

Author SummaryCancers often develop as a consequence of deregulated expression of key factors that operate during normal development. T-cell factor 1 (Tcf1) has an established role in the nuclear response to Wnt signaling during normal T-cell development in the thymus. Here we show in mice that the absence of Tcf1 can trigger tumorigenesis. As expected from previous work, lack of Tcf1 results in a small thymus with several partial blocks in T-cell development in the thymus. Surprisingly, we observe that a large proportion of Tcf1−/− mice spontaneously develop thymic lymphomas. Thorough investigation of these thymic-derived tumors revealed that the mechanism underlying these lymphomas is, paradoxically, increased levels of Wnt-signaling. We propose that Wnt-signaling in these tumors is mediated by up-regulated expression of the Tcf1-homologue, Lef1, and specifically its long isoform. Furthermore, we have evidence to propose that in a normal thymus, short isoforms of Tcf1 that cannot respond to Wnt signals act as repressors of Lef1-mediated Wnt-signaling. Thus, we propose that Tcf1 has a dual function developing T cells in mice: it functions as a T-cell–specific tumor suppressor gene in addition to its established role as a transcriptional activator of Wnt-induced proliferation. Whether loss of function of Tcf-1 as a tumor suppressor gene actually occurs in human T-cell lymphoblastic leukemias is currently under investigation.