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

Autor:	Sakoda T; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan., Kikushige Y; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan., Miyamoto T; Department of Hematology, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan., Irifune H; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan., Harada T; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan., Hatakeyama K; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan., Kunisaki Y; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan., Kato K; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan., Akashi K; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2023 May 23; Vol. 7 (10), pp. 2053-2065.
DOI:	10.1182/bloodadvances.2022008405
Abstrakt:	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. (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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