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Type: Journal article
Title: The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T cell development and malignancy
Author: Yu, S.
Zhou, X.
Steinke, F.
Liu, C.
Chen, S.
Zagorodna, O.
Jing, X.
Yokota, Y.
Meyerholz, D.
Mullighan, C.
Knudson, C.
Zhao, D.
Xue, H.
Citation: Immunity, 2012; 37(5):813-826
Publisher: Cell Press
Issue Date: 2012
ISSN: 1074-7613
Statement of
Shuyang Yu, Xinyuan Zhou, Farrah C. Steinke, Chengyu Liu, Shann-Ching Chen, Oksana Zagorodna, Xuefang Jing, Yoshifumi Yokota, David K. Meyerholz, Charles G. Mullighan, C. Michael Knudson, Dong-Mei Zhao and Hai-Hui Xue
Abstract: 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.
Keywords: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Rights: ©2012 Elsevier Inc.
DOI: 10.1016/j.immuni.2012.08.009
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