Lef1 Is a Critical Mediator of Wnt/β-Catenin Signaling in T-Cell Acute Lymphoblastic Leukemia (T-ALL)

T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy characterized by an uncontrolled proliferation of immature T-cells. While current therapies cure ~80% of pediatric patients, adults fare more poorly with ~40% overall survival. Refractory cases and relapses are presumably due to the ineffective targeting of leukemia stem cells (LSC), previously described in human and in mouse models of T-ALL, and thought to be resistant to standard treatments.

Recently, we have reported that active signaling through the Wnt/β-catenin pathway is a defining feature of LSC in T-ALL, and that interruption of this signaling pathway abrogates disease propagation in vivo. Using an integrated, real-time reporter of Wnt/β-catenin signaling (7TGC; composed of 7 Tcf/Lef-binding sites upstream of a minimal promoter and GFP marker), we identified leukemia-initiating cell (LIC) activity to reside asymmetrically within the minor proportion of Wnt-active, GFP+ cells in primary mouse NOTCH1-induced T-cell leukemias. Moreover, inducible deletion of β-catenin in this context eliminated LIC activity.

Here, we report that LIC activity in this Wnt-active subpopulation is dependent on Lef1. Using Lef1^loxP/loxP animals, we show that inducible Cre-mediated deletion of Lef1 in established leukemias extinguishes both Wnt/GFP reporter expression and LIC activity. To explore mechanisms underlying asymmetry of LIC activity within the tumor population, we have also investigated the differential expression of various Lef1 protein isoforms in Wnt-active (GFP+) vs. Wnt-inactive (GFP-) leukemic subsets and assessed their function in supporting LIC activity. These results suggest that β-catenin acts via Lef1 to support asymmetric LIC activity within the Wnt-active subset of leukemia cells.