The role of Lef1 in T cell development and lymphomagenesis

T cell precursor acute lymphoblastic leukemia (T-ALL) is a malignancy arising from developing thymocytes. One main mechanism leading to T-ALL formation is the inhibition of E protein activity, which also abrogates normal T cell development before disease onset. In the absence of E2A, abnormal thymocytes can escape beta-selection and become precursors of T cell lymphomas in E2A -/- mice. We have recently demonstrated that the transcription factor Lef1 promotes the survival of E2A-/- T cell lymphomas as a direct target gene of Notch1. Here I show that Lef1 expression is elevated in E2A-/- DN3 thymocytes prior to the onset of lymphoma and may compensate for some of the deficiencies resulting from the absence of E2A. Remarkably, ectopic Lef1 expression accelerates T cell lineage specification in wild type fetal liver progenitors in vitro , and more importantly, it can also specify the T cell program in fetal liver progenitors from E2A-/- embryos. Moreover, E2A-/- DN3s hyperproliferate in vivo and excess Lef1 expression can promote aberrant proliferation of wild type DN3s in vitro. Thus, while Lef1 may provide a selective pressure for a subset of E2A -/- thymocyte progenitors, it may also facilitate a premalignant state in DN3 thymocytes. Indeed, Lef1 expression influences many components of the thymopoietic network that are also critical mediators of T-ALL, primarily in the promotion of cell cycle entry. Thus Lef1 is in a unique position to tip the balance of processes within thymocyte progenitors from normal developmental progression to lymphomagenesis.