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TIM-3 signaling hijacks the canonical Wnt/ß-catenin pathway to maintain cancer stemness in acute myeloid leukemia.
Sakoda, Teppei; Kikushige, Yoshikane; Miyamoto, Toshihiro; Irifune, Hidetoshi; Harada, Takuya; Hatakeyama, Kiwamu; Kunisaki, Yuya; Kato, Koji; Akashi, Koichi.
Afiliação
  • Sakoda T; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
  • Kikushige Y; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
  • Miyamoto T; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
  • Irifune H; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
  • Harada T; Department of Hematology, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
  • Hatakeyama K; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
  • Kunisaki Y; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
  • Kato K; Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
  • Akashi K; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
Blood Adv ; 7(10): 2053-2065, 2023 05 23.
Article em En | MEDLINE | ID: mdl-36745103
ABSTRACT
The activation of ß-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 ß-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 ß-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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Via de Sinalização Wnt Limite: Humans Idioma: En Revista: Blood Adv Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Via de Sinalização Wnt Limite: Humans Idioma: En Revista: Blood Adv Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Japão