Exploring the stage-specific roles of Tcf-1 in T cell development and malignancy at single-cell resolution |
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Authors: | Fang Wang Zhihong Qi Yingpeng Yao Guotao Yu Tao Feng Tianyan Zhao Hai-Hui Xue Yaofeng Zhao Peng Jiang Li Bao Shuyang Yu |
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Institution: | 1.State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Road 2, 100193 Beijing, China ;2.Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242 USA ;3.Regenerative Biology Laboratory, Morgridge Institute for Research, Madison, WI 53707 USA ;4.Department Hematology, Beijing Jishuitan Hospital, 100096 Beijing, China |
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Abstract: | Tcf-1 (encoded by Tcf7) not only plays critical roles in promoting T cell development and differentiation but also has been identified as a tumor suppressor involved in preventing T cell malignancy. However, the comprehensive mechanisms of Tcf-1 involved in T cell transformation remain poorly understood. In this study, Tcf7fl/fl mice were crossed with Vav-cre, Lck-cre, or Cd4-cre mice to delete Tcf-1 conditionally at the beginning of the HSC, DN2–DN3, or DP stage, respectively. The defective T cell development phenotypes became gradually less severe as the deletion stage became more advanced in distinct mouse models. Interestingly, consistent with Tcf7−/− mice, Tcf7fl/flVav-cre mice developed aggressive T cell lymphoma within 45 weeks, but no tumors were generated in Tcf7fl/flLck-cre or Tcf7fl/flCd4-cre mice. Single-cell RNA-seq (ScRNA-seq) indicated that ablation of Tcf-1 at distinct phases can subdivide DN1 cells into three clusters (C1, C2, and C3) and DN2–DN3 cells into three clusters (C4, C5, and C6). Moreover, Tcf-1 deficiency redirects bifurcation among divergent cell fates, and clusters C1 and C4 exhibit high potential for leukemic transformation. Mechanistically, we found that Tcf-1 directly binds and mediates chromatin accessibility for both typical T cell regulators and proto-oncogenes, including Myb, Mycn, Runx1, and Lyl1 in the DN1 phase and Lef1, Id2, Dtx1, Fyn, Bcl11b, and Zfp36l2 in the DN2–DN3 phase. The aberrant expression of these genes due to Tcf-1 deficiency in very early T cells contributes to subsequent tumorigenesis. Thus, we demonstrated that Tcf-1 plays stage-specific roles in regulating early thymocyte development and transformation, providing new insights and evidence for clinical trials on T-ALL leukemia. |
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Keywords: | ScRNA-seq Tcf-1 T cell Lymphoma development Malignancy Leukemic transformation |
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