title: The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T cell development and malignancy.
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.
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Yu
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Zhou
authors.forename: Farrah C
authors.initials: FC
authors.lastname: Steinke
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.forename: Shann-Ching
authors.initials: SC
authors.lastname: Chen
authors.forename: Oksana
authors.initials: O
authors.lastname: Zagorodna
authors.forename: Xuefang
authors.initials: X
authors.lastname: Jing
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Yokota
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: C Michael
authors.initials: CM
authors.lastname: Knudson
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Zhao
authors.forename: Hai-Hui
authors.initials: HH
authors.lastname: Xue
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051538:Hepatocyte Nuclear Factor 1-alpha; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D060168:Thymocytes / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D051880:Receptors, Notch; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human; D014157:Transcription Factors