The nuclear effector of Wnt-signaling, Tcf1, functions as a T-cell-specific tumor suppressor for development of lymphomas
| Autor: | Ugur Ozbek, Machteld M. Tiemessen, Martijn H. Brugman, Daniela C.F. Salvatori, Tom Schonewille, Farbod Famili, Hans Clevers, Jules P.P. Meijerink, Jacques J.M. van Dongen, Miranda R. M. Baert, Frank J. T. Staal |
|---|---|
| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Lymphoma
T-Lymphocytes Hematologic Cancers and Related Disorders Mice Genes Reporter Protein Isoforms Genes Tumor Suppressor Hepatocyte Nuclear Factor 1-alpha Neoplasm Metastasis Receptor Notch1 Biology (General) Promoter Regions Genetic Wnt Signaling Pathway Cells Cultured Oligonucleotide Array Sequence Analysis Thymic Lymphoma Thymocytes T Cells General Neuroscience Wnt signaling pathway LRP5 Hematology Acute Lymphoblastic Leukemia Gene Expression Regulation Neoplastic Medicine General Agricultural and Biological Sciences Research Article Transcriptional Activation Tumor suppressor gene Lymphoid Enhancer-Binding Factor 1 QH301-705.5 Immune Cells Green Fluorescent Proteins Immunology Thymus Gland Biology Transfection General Biochemistry Genetics and Molecular Biology Axin Protein Leukemias medicine AXIN2 Animals Genetic Predisposition to Disease Transcription factor General Immunology and Microbiology medicine.disease Hematopoiesis Mice Inbred C57BL Cancer research Lymphoid enhancer-binding factor 1 |
| Zdroj: | PLoS Biology, Vol 10, Iss 11, p e1001430 (2012) PLoS Biology, 10(11). Public Library of Science PLoS Biology |
| ISSN: | 1544-9173 |
| Popis: | Tcf1 is known to function as a transcriptional activator of Wnt-induced proliferation during T cell development in the thymus. Evidence for an additional contrasting role for Tcf1 as a T-cell specific tumor suppressor gene is now presented. The HMG-box factor Tcf1 is required during T-cell development in the thymus and mediates the nuclear response to Wnt signals. Tcf1−/− mice have previously been characterized and show developmental blocks at the CD4−CD8− double negative (DN) to CD4+CD8+ double positive transition. Due to the blocks in T-cell development, Tcf1−/− mice normally have a very small thymus. Unexpectedly, a large proportion of Tcf1−/− mice spontaneously develop thymic lymphomas with 50% of mice developing a thymic lymphoma/leukemia at the age of 16 wk. These lymphomas are clonal, highly metastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and have high expression of Wnt target genes Lef1 and Axin2. In wild-type thymocytes, Tcf1 is higher expressed than Lef1, with a predominance of Wnt inhibitory isoforms. Loss of Tcf1 as repressor of Lef1 leads to high Wnt activity and is the initiating event in lymphoma development, which is exacerbated by activating Notch1 mutations. Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events. Tcf1 deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due to lack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1. Tcf1 therefore functions as a T-cell–specific tumor suppressor gene, besides its established role as a Wnt responsive transcription factor. Thus, Tcf1 acts as a molecular switch between proliferative and repressive signals during T-lymphocyte development in the thymus. Author Summary Cancers 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|