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Exploring the stage-specific roles of Tcf-1 in T cell development and malignancy at single-cell resolution

Cellular & Molecular Immunology 2021年第3期18卷 644-659页

作者： Fang Wang Zhihong Qi Yingpengao Guotao Yu Tao Feng Tianyan Zhao Hai-Hui Xue Yaofeng Zhao Peng Jiang Li Bao Shuyang Yu State Key Laboratory of Agrobiotechnology College of Biological SciencesChina Agricultural UniversityYuanmingyuan West Road 2100193 BeijingChina Department of Microbiology and Immunology Carver College of MedicineUniversity of IowaIowa CityIA 52242USA Regenerative Biology Laboratory Morgridge Institute for ResearchMadisonWI 53707USA Department Hematology Beijing Jishuitan Hospital100096 BeijingChina

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 ***,the comprehensive mechanisms of Tcf-1 involved in T cell transformation remain poorly *** this study,Tcf7^(fl/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,*** defective T cell development phenotypes became gradually less severe as the deletion stage became more advanced in distinct mouse ***,consistent with Tcf7^(-/-)mice,Tcf^(fl/fl)Vav-cre mice developed aggressive T cell lymphoma within 45 weeks,but no tumors were generated in Tcf7^(fl/fl)Lck-cre or Tcf^(fl/fl)CdA-cre ***-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 ***,we found that Tcf-1 directly binds and mediates chromatin accessibility for both typical T cell regulators and proto-oncogenes#including Myb,Mycn,Runxl,and Lyl1 in the DN1 phase and Lefb ld2,Dtxb Fyn,Bclllb,and Zfp36l2 in the DN2-DN3 *** aberrant expression of these genes due to Tcf-1 deficiency in very early T cells contributes to subsequent ***,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.

关键词： ScRNA-seq Tcf-1 T cell lymphoma development Malignancy Leukemic transformation

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