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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
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
-
Hepatocyte Nuclear Factor 1-alpha
-
Humans
-
Inhibitor of Differentiation Protein 2 / genetics
-
Inhibitor of Differentiation Protein 2 / metabolism
-
Lymphoid Enhancer-Binding Factor 1 / genetics
-
Lymphoid Enhancer-Binding Factor 1 / immunology
-
Lymphoid Enhancer-Binding Factor 1 / metabolism*
-
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
-
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 / genetics
-
Transcription Factors / metabolism*
-
Up-Regulation / genetics
Substances
-
CD4 Antigens
-
CD8 Antigens
-
Hepatocyte Nuclear Factor 1-alpha
-
Hnf1a protein, mouse
-
ID2 protein, human
-
Inhibitor of Differentiation Protein 2
-
Lef1 protein, mouse
-
Lymphoid Enhancer-Binding Factor 1
-
Receptors, Notch
-
T Cell Transcription Factor 1
-
TCF7 protein, human
-
Transcription Factors