The TCF-1 and LEF-1 Transcription Factors Have Cooperative and Opposing Roles in T Cell Development and Malignancy

• Published in: Immunity (Cambridge, Mass.) Mass.), 2012-11, Vol.37 (5), p.813-826
• Main Authors: Yu, Shuyang, Zhou, Xinyuan, Steinke, Farrah C., Liu, Chengyu, Chen, Shann-Ching, Zagorodna, Oksana, Jing, Xuefang, Yokota, Yoshifumi, Meyerholz, David K., Mullighan, Charles G., Knudson, C. Michael, Zhao, Dong-Mei, Xue, Hai-Hui
• Format: Article
• Language: English
• Subjects: Animals; CD4 Antigens - genetics; CD4 Antigens - metabolism; CD8 Antigens - genetics; CD8 Antigens - metabolism; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - immunology; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Gene expression; Hepatocyte Nuclear Factor 1-alpha; Humans; Inhibitor of Differentiation Protein 2 - genetics; Inhibitor of Differentiation Protein 2 - metabolism; Kinases; Lymphoid Enhancer-Binding Factor 1 - genetics; Lymphoid Enhancer-Binding Factor 1 - immunology; Lymphoid Enhancer-Binding Factor 1 - metabolism; Lymphoma; Lymphoma, T-Cell - genetics; Lymphoma, T-Cell - metabolism; Mice; Mice, Inbred C57BL; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Receptors, Notch - genetics; Receptors, Notch - metabolism; Rodents; Statistical analysis; T Cell Transcription Factor 1 - genetics; T Cell Transcription Factor 1 - immunology; T Cell Transcription Factor 1 - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Thymocytes - metabolism; Thymocytes - pathology; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Up-Regulation - genetics
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2012.08.009

The TCF-1 and LEF-1 transcription factors are known to play critical roles in normal thymocyte development. Unexpectedly, we found that TCF-1-deficient (Tcf7−/−) mice developed aggressive T cell malignancy, resembling human T cell acute lymphoblastic leukemia (T-ALL). LEF-1 was aberrantly upregulated in premalignant Tcf7−/− early thymocytes and lymphoma cells. We further demonstrated that TCF-1 directly repressed LEF-1 expression in early thymocytes and that conditional inactivation of Lef1 greatly delayed or prevented T cell malignancy in Tcf7−/− mice. In human T-ALLs, an early thymic progenitor (ETP) subtype was associated with diminished TCF7 expression, and two of the ETP-ALL cases harbored TCF7 gene deletions. We also showed that TCF-1 and LEF-1 were dispensable for T cell lineage commitment but instead were required for early thymocytes to mature beyond the CD4−CD8− stage. TCF-1 thus has dual roles, i.e., acting cooperatively with LEF-1 to promote thymocyte maturation while restraining LEF-1 expression to prevent malignant transformation of developing thymocytes. [Display omitted] ► TCF-1 and LEF-1 have both cooperative and opposing roles during T cell development ► TCF-1 and LEF-1 are required for β-selection but not T cell lineage commitment ► TCF-1 directly restrains LEF-1 expression to prevent thymocyte transformation ► ETP-ALLs are associated with decreased TCF1 expression and harbor TCF7 gene deletion