| First Author | Wang F | Year | 2021 |
| Journal | Cell Mol Immunol | Volume | 18 |
| Issue | 3 | Pages | 644-659 |
| PubMed ID | 32868912 | Mgi Jnum | J:331299 |
| Mgi Id | MGI:7386950 | Doi | 10.1038/s41423-020-00527-1 |
| Citation | Wang F, et al. (2021) Exploring the stage-specific roles of Tcf-1 in T cell development and malignancy at single-cell resolution. Cell Mol Immunol 18(3):644-659 |
| abstractText | 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, 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, 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, Tcf7(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 Tcf7(fl/fl)Cd4-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. |
