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Immunity. 2012 Nov 16;37(5):813-26. doi: 10.1016/j.immuni.2012.08.009. Epub 2012 Oct 25.

The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T cell development and malignancy.

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1
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.

Erratum in

  • Immunity. 2014 Jan 16;40(1):166.

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.

PMID:
23103132
PMCID:
PMC3501598
DOI:
10.1016/j.immuni.2012.08.009
[Indexed for MEDLINE]
Free PMC Article

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