Journal article
The TCF-1 and LEF-1 Transcription Factors Have Cooperative and Opposing Roles in T Cell Development and Malignancy
Immunity (Cambridge, Mass.), Vol.37(5), pp.813-826
11/16/2012
DOI: 10.1016/j.immuni.2012.08.009
PMID: 23103132
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.
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► 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
Details
- Title: Subtitle
- The TCF-1 and LEF-1 Transcription Factors Have Cooperative and Opposing Roles in T Cell Development and Malignancy
- Creators
- Shuyang Yu - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAXinyuan Zhou - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAFarrah C Steinke - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAChengyu Liu - Transgenic Core Facility, NHLBI, NIH, Bethesda, MD 20892, USAShann-Ching Chen - Department of Pathology, St Jude Children's Research Hospital, Memphis, TN 38105, USAOksana Zagorodna - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAXuefang Jing - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAYoshifumi Yokota - Division of Molecular Genetics, Department of Biochemistry and Bioinformatic Sciences, School of Medicine, University of Fukui, Fukui 910-1193, JapanDavid K Meyerholz - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USACharles G Mullighan - Department of Pathology, St Jude Children's Research Hospital, Memphis, TN 38105, USAC. Michael Knudson - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADong-Mei Zhao - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAHai-Hui Xue - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Immunity (Cambridge, Mass.), Vol.37(5), pp.813-826
- DOI
- 10.1016/j.immuni.2012.08.009
- PMID
- 23103132
- NLM abbreviation
- Immunity
- ISSN
- 1074-7613
- eISSN
- 1097-4180
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 11/16/2012
- Academic Unit
- Microbiology and Immunology; Pathology; Radiation Oncology
- Record Identifier
- 9984047987602771
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