Seminar

Inhibition of Wnt5a/Fzd2 pathway abolishes T-cell acute lymphoblastic leukemia generation

Marta Irigoyen, PhD

T-cell acute lymphoblastic leukemia (T-ALL) is a malignant disorder of immature T-cells. Although current therapies can temporarily suppress the disease, high recurrence occurs because actual treatments do not target leukemia-initiating cells (LIC), a cell subpopulation able to repopulate the tumor. We previously demonstrated that Calcineurin (Cn), a serine-threonine phosphatase, is a critical effector of signaling pathways intrinsic to LIC activity in T-ALL. Due to the toxicity of the existing Cn inhibitors, the search for upstream pathways involved in Cn activation is essential. In this work, we use an activated NOTCH1 (ICN1)-induced mouse T-ALL and human T-ALL cell xenograft models to demonstrate that Wnt5a (a non-canonical Wnt ligand produced by bone marrow stromal cells) activates the Cn/NFAT axis through the interaction with the receptor Fzd2. Moreover, our results show that Fzd2 silencing decreases the proliferative and survival capabilities of both murine and human leukemic cells and inhibits their ability to generate leukemia. In conclusion, our results identify for the first time a new signaling pathway regulating LIC activity, and propose Wnt5a/Fzd2 axis as an attractive therapeutic target to treat recidives in refractory T-ALL.