[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-383635-105":3,"detail-sidebar-cat-0-en-105":73,"doc-detail-383635-en":122},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":66,"head_meta":68,"extra_data":70,"updated_unix":72},105,"en","tim-3-signaling-hijacks-the-canonical-wnt-catenin-pathway-to-maintain-cancer-stemness-in-acute-myeloid-leukemia","TIM-3 signaling hijacks the canonical Wnt/β-catenin pathway to maintain cancer stemness in acute myeloid leukemia","","TIM-3/Gal-9 autocrine signaling drives canonical Wnt activation to sustain leukemic stem cells in acute myeloid leukemia (AML). Gal-9 engagement activates TIM-3 and recruits HCK, a Src-family kinase enriched in AML LSCs, which phosphorylates p120-catenin to assemble an LRP6 signalosome and hijack the canonical Wnt pathway. β-catenin activation promotes self-renewal and propagation of LSCs, with activity strongest in immature LSCs rather than differentiated blasts. These findings support TIM-3/HCK/p120-catenin axis as a selective therapeutic target.",{"@graph":14,"@context":65},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/tim-3-signaling-hijacks-the-canonical-wnt-catenin-pathway-to-maintain-cancer-stemness-in-acute-myeloid-leukemia/383635/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/tim-3-signaling-hijacks-the-canonical-wnt-catenin-pathway-to-maintain-cancer-stemness-in-acute-myeloid-leukemia/383635.png","ImageObject",300,407,{"name":42,"@type":43},"Riley","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-03","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",10,{"@type":57,"mainEntity":58},"FAQPage",[59],{"name":60,"@type":61,"acceptedAnswer":62},"What evidence links TIM-3/HCK/p120-catenin signaling to selective LSC eradication?","Question",{"text":63,"@type":64},"The TIM-3/HCK/p120-catenin axis is principally active in immature AML LSCs rather than differentiated blasts or exhausted T cells. The data suggest constitutive β-catenin activation via autocrine TIM-3 signaling and indicate molecules in this axis as critical targets for selective elimination of LSCs without impairing normal HSCs.","Answer","https://schema.org",{"og:url":32,"og:type":67,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":69,"canonical":32},"index,follow",{"doc_id":71,"site_id":7},383635,1790304953,{"code":4,"msg":74,"data":75},"success",[76,80,84,88,93,98,102,107,112,115,118],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":77,"show_sort_weight":78,"slug":79},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":81,"show_sort_weight":82,"slug":83},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Exam",70,"exam",{"id":89,"doc_module":4,"doc_module_name":25,"category_name":90,"show_sort_weight":91,"slug":92},5,"Comic",60,"comic",{"id":94,"doc_module":4,"doc_module_name":25,"category_name":95,"show_sort_weight":96,"slug":97},6,"Technology",50,"technology",{"id":99,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":100,"slug":101},7,40,"healthcare",{"id":103,"doc_module":4,"doc_module_name":25,"category_name":104,"show_sort_weight":105,"slug":106},8,"Research & Report",30,"research-report",{"id":108,"doc_module":4,"doc_module_name":25,"category_name":109,"show_sort_weight":110,"slug":111},9,"Religion & Spirituality",20,"religion-spirituality",{"id":110,"doc_module":4,"doc_module_name":25,"category_name":113,"show_sort_weight":110,"slug":114},"World Cup","world-cup",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":55,"slug":117},"Lifestyle","lifestyle",{"id":119,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":89,"slug":121},19,"General","general",{"code":4,"msg":74,"data":123},{"doc_id":71,"user_id":124,"nickname":42,"user_avatar":125,"doc_module":4,"category_id":99,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":126,"file_id":127,"file_url":128,"file_type":129,"file_size":130,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":131,"language":132,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":133,"faqs":134,"seo_title":135,"seo_description":12,"update_tm":136,"read_time":137},1374391975076,"https://ap-avatar.wpscdn.com/avatar/14000253ca4ec9f6853?x-image-process=image/resize,m_fixed,w_180,h_180&k=1783305029341752051","REGULAR ARTICLE  \nTIM-3 signaling hijacks the canonical Wnt/β-catenin pathway to maintain cancer stemness in acute myeloid leukemia  \nTeppei Sakoda, 1, 2 Yoshikane Kikushige, 1, 2 Toshihiro Miyamoto,3 Hidetoshi Irifune, 1 Takuya Harada, 1 Kiwamu Hatakeyama, 1 Yuya Kunisaki,2 Koji Kato, 1 and Koichi Akashi 1, 2  \n1 Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan; 2 Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan; and 3 Department of Hematology, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan  \nKey Points  \n• TIM-3/Gal-9 autocrine loop hijacks and constitutively activates canonical Wnt pathway in AML LSCs.  \n• To hijack canonical Wnt pathway, HCK and p120-catenin, highly expressed on AML LSCs, play crucial roles in signal transduction of TIM-3 .  \nThe 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.  \nIntroduction  \nAcute myeloid leukemia (AML) is one of the most common hematologic malignancies. Previous studies have shown that AML is derived from a fraction of stem cells called leukemic stem cells (LSCs), which have self-renewal and high propagation activity. We have reported that the T-cell immunoglobulin mucin-3 (TIM-3) is expressed on the surface of LSCs in >90% of patients with AML but is never found within the normal hematopoietic stem cell (HSC) population.1-3 TIM-3 is a type 1 cell-surface glycoprotein,4 also expressed in a fraction of T cells, natural killer (NK) cells, monocytes, and dendritic cells (DCs), and its signaling generally plays immune modulatory roles in these cells.5,6 In contrast, the majority of AML LSCs express TIM-3,3, 7,8 and a preclinical study in a xenograft model has shown that engrafted human AML cells were eradicated by administration of cytotoxic antihuman TIM-3 antibodies,  \nSubmitted 22 June 2022; accepted 26 January 2023; prepublished online on Blood Advances First Edition 6 February 2023. [https://doi.org/10.1182/](https://doi.org/10.1182/)[ ](https://doi.org/10.1182/)[bloodadvances.2022008405](bloodadvances.2022008405.)[.](bloodadvances.2022008405.)  \nExpression microarray data are available in the Gene Expression Omnibus database (accession number GSE130328) . All materials are available commercially or can be derived using the methods described in this article.  \nData are available on request from the corresponding author, Yoshikane Kikushige ([kikushige.yoshikane.726@m.kyushu-u.ac.jp](kikushige.yoshikane.726@m.kyushu-u.ac.jp)).  \nThe full-text version of this article contains a data ","cbCaiuXOqsVKYbiK","https://ap.wps.com/l/cbCaiuXOqsVKYbiK","pdf",2086236,13,"English","# Key Points\n# Introduction\n## Leukemic stem cells and TIM-3 in AML\n## Galectin-9/TIM-3 signaling and β-catenin accumulation\n## Canonical Wnt pathway and β-catenin regulation","[{\"question\":\"What evidence links TIM-3/HCK/p120-catenin signaling to selective LSC eradication?\",\"answer\":\"The TIM-3/HCK/p120-catenin axis is principally active in immature AML LSCs rather than differentiated blasts or exhausted T cells. The data suggest constitutive β-catenin activation via autocrine TIM-3 signaling and indicate molecules in this axis as critical targets for selective elimination of LSCs without impairing normal HSCs.\"}]","TIM-3 signaling hijacks the canonical Wnt/β-catenin pathway to maintain cancer stemness in acute myeloid leukemia | PDF",1790258494,33]