Tcf3, also known as E2A, is a transcription factor that belongs to the TCF/LEF family. It contributes to early lymphocyte differentiation and is involved in multiple biological processes, such as oogenesis, folliculogenesis, and regulation of the Wnt signaling pathway. It also plays a role in the development of the immune system and in tumorigenesis [1,2,6,7].

In mice, Tcf3 and Tcf12 are crucial regulators of oogenesis. Deficiency of Tcf3 impairs activation of key oocyte genes and folliculogenesis [1].

In humans, germline monoallelic dominant negative and biallelic loss-of-function null Tcf3 mutations cause a fully penetrant severe immunodeficiency. Monoallelic loss-of-function Tcf3 mutations result in B-cell defects, reduced serum immunoglobulin levels, and a dysregulated transcriptome, leading to immunodeficiency. Tcf3+/- mice partially recapitulate the human phenotype, highlighting the differences between Tcf3 in humans and mice [2].

In the context of cancer, Tcf3 gene fusions occur in 5%-11% of acute lymphoblastic leukemia (ALL) patients. The TCF3-HLF fusion gene is associated with a very poor prognosis, while the TCF3-PBX1 fusion gene is associated with a relatively good prognosis. High molecular heterogeneity of Tcf3 gene rearrangement in pediatric B-cell precursor ALL was demonstrated [3,4].

In Burkitt lymphoma, inhibition of SHMT2, an enzyme in one-carbon metabolism, leads to autophagic degradation of Tcf3, disrupting the Tcf3-controlled tonic B-cell receptor signaling essential for cell survival [5].

In glioma, Tcf3 activates DNMT1 transcription, which in turn represses SFRP1 expression, regulating the Wnt signaling pathway [7].

In recurrent pregnancy loss (RPL), Tcf3 is downregulated in decidual tissues. Tcf3 knockdown in human endometrial stromal cells inhibits proliferation and promotes migration, potentially through the mitogen-activated protein kinase pathway [8].

In conclusion, Tcf3 is a multifunctional transcription factor. Its deficiency in mice reveals its importance in oogenesis and folliculogenesis. In humans, Tcf3 mutations are associated with immunodeficiency and different cancer types, such as ALL, Burkitt lymphoma, and glioma. The study of Tcf3 using gene knockout and other genetic models helps to understand its role in biological processes and disease mechanisms, providing potential targets for diagnosis and treatment in immunodeficiency and cancer-related disease areas.