TIM-3 signaling hijacks the canonical Wnt/β-catenin pathway to maintain cancer stemness in acute myeloid leukemia.

The activation of β-catenin plays critical roles in normal stem cell function, and when aberrantly activated, maintenance and enhancement of cancer stemness in many solid cancers. The aberrant β-catenin activation is also observed in acute myeloid leukemia (AML), and crucially contributes to self-renewal and propagation of leukemic stem cells (LSCs) regardless of mutations in contrast to such solid tumors. In this study, we showed that the AML-specific autocrine loop constituted of T-cell immunoglobulin mucin-3 (TIM-3) and its ligand, galectin-9 (Gal-9), drives the canonical Wnt pathway to stimulate self-renewal and propagation of leukemic stem cells (LSCs), independent of Wnt ligands. Gal-9 ligation activates the cytoplasmic Src homology 2 (SH2) domain of TIM-3 to recruit hematopoietic cell kinase (HCK), an Src family kinase highly expressed in LSCs but not in HSCs, and HCK phosphorylates p120-catenin to promote formation of the LDL-receptor related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis is principally employed in immature LSCs compared to TIM-3-expressed differentiated AML blasts and exhausted T-cells. These data suggest that human AML LSCs constitutively activates β-catenin through utilizing the autocrine TIM-3/HCK/p120-catenin signaling, and that molecules related to this signaling axis should be critical targets for selective eradication of LSCs without impairing normal HSCs.