Sakoda Teppei, Kikushige Yoshikane
Center for Cellular and Molecular Medicine, Kyushu University Hospital.
Rinsho Ketsueki. 2023;64(6):547-552. doi: 10.11406/rinketsu.64.547.
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 CD34CD38 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.
急性髓系白血病（AML）是源自自我更新且高度增殖的白血病干细胞（LSC）的最常见血液系统恶性肿瘤之一。我们之前通过比较LSC和造血干细胞（HSC）的基因表达谱，将T细胞免疫球蛋白粘蛋白-3（TIM-3）鉴定为AML LSC特异性表面分子。TIM-3表达能在CD34CD38干细胞亚群中清晰地区分LSC和HSC。此外，AML细胞以自分泌方式分泌半乳糖凝集素-9（Gal-9，一种TIM-3配体），导致持续性TIM-3信号传导，通过β-连环蛋白积累维持LSC自我更新能力。在本研究中，我们研究了TIM-3信号传导的LSC特异性机制。我们发现TIM-3信号传导驱动经典Wnt通路，该通路独立于Wnt配体，以维持LSC中的癌干性。Gal-9连接激活TIM-3的细胞质Src同源2（SH2）结合结构域，以募集造血细胞激酶（HCK），这是一种在LSC中高表达的Src家族激酶。HCK磷酸化p120-连环蛋白以促进低密度脂蛋白受体相关蛋白6（LRP6）信号小体的形成，从而劫持经典Wnt通路。与表达TIM-3的耗竭T细胞相比，这种TIM-3/HCK/p120-连环蛋白轴主要在未成熟LSC中起作用。
