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Sakoda T, Kikushige Y, Miyamoto T, Irifune H, Harada T, Hatakeyama K, Kunisaki Y, Kato K, Akashi K., TIM-3 signaling hijacks the canonical Wnt/β-catenin pathway to maintain cancer stemness in acute myeloid leukemia, Blood Advances, 10.1182/bloodadvances.2022008405., 7, 10, 2053-2065, 2023.05, The activation of β-catenin plays critical roles in normal stem cell function, and, when aberrantly activated, the maintenance and enhancement of cancer stemness in many solid cancers. 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 with such solid tumors. In this study, we showed that the AML-specific autocrine loop comprised 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 LSCs, independent of Wnt ligands. Gal-9 ligation activates the cytoplasmic Src homology 2 domain of TIM-3 to recruit hematopoietic cell kinase (HCK), a 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 active in immature LSCs compared with TIM-3-expressed differentiated AML blasts and exhausted T cells. These data suggest that human AML LSCs constitutively activates β-catenin via 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.. |
