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Sakoda, Teppei; Kikushige, Yoshikane
Rinshō ketsueki, 2023, Letnik: 64, Številka: 6Journal Article
Acute myeloid leukemia (AML) is one of the most common hematologic malignancies derived from self-renewing and highly propagating leukemic stem cells (LSCs). We have previously identified T-cell immunoglobulin mucin-3 (TIM-3) as an AML LSC-specific surface molecule by comparing the gene expression profiles of LSCs and hematopoietic stem cells (HSCs). TIM-3 expression clearly discriminates LSCs from HSCs within the CD34 CD38 stem cell fraction. Furthermore, AML cells secrete galectin-9 (Gal-9, a TIM-3 ligand) in an autocrine manner, resulting in constitutive TIM-3 signaling, which maintains LSC self-renewal capacity through β-catenin accumulation. In this study, we investigated the LSC-specific mechanisms of TIM-3 signaling. We found that TIM-3 signaling drove the canonical Wnt pathway, which was independent of Wnt ligands, to maintain cancer stemness in LSCs. Gal-9 ligation activated the cytoplasmic Src homology 2 (SH2) binding domain of TIM-3 to recruit hematopoietic cell kinase (HCK), a Src family kinase that is highly expressed in LSCs. HCK phosphorylated p120-catenin to promote the formation of the LDL receptor-related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis was employed principally in immature LSCs compared to TIM-3-expressing exhausted T-cells.
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