Schematic summary of a novel molecular mechanisms of the hijacking of the canonical Wnt pathway by TIM-3 signaling in AML LSCs. The schema shows how TIM-3 signaling induces constitutively canonical Wnt pathway activation and aberrant accumulation of β-catenin in AML-LSCs. As shown in the left panel, β-catenin is constantly destroyed by the β-catenin degradation complex in the absence of canonical Wnt pathway activation. As shown in the right panel, in AML, a TIM-3/Gal-9 autocrine loop constitutively recruits and activates HCK, leading to the induction of p120-catenin phosphorylation. The activated p120-catenin initiates LRP6 signalosome formation to inhibit the function of the β-catenin degradation complex, leading to the aberrant accumulation of β-catenin in AML cells. Through the use of LSCs-specific molecules such as TIM-3, HCK, and p120-catenin, the AML LSCs hijack the canonical Wnt pathway.