JAM3 maintains leukemia-initiating cell self-renewal through LRP5/AKT/β-catenin/CCND1 signaling

Yaping Zhang, Fangzhen Xia, Xiaoye Liu, Zhuo Yu, Li Xie, Ligen Liu, Chiqi Chen, Haishan Jiang, Xiaoxin Hao, Xiaoxiao He, Feifei Zhang, Hao Gu, Jun Zhu, Haitao Bai, Chengcheng Zhang, Guo Qiang Chen, Junke Zheng

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Abstract

Leukemia-initiating cells (LICs) are responsible for the initiation, development, and relapse of leukemia. The identification of novel therapeutic LIC targets is critical to curing leukemia. In this report, we reveal that junctional adhesion molecule 3 (JAM3) is highly enriched in both mouse and human LICs. Leukemogenesis is almost completely abrogated upon Jam3 deletion during serial transplantations in an MLL-AF9-induced murine acute myeloid leukemia model. In contrast, Jam3 deletion does not affect the functions of mouse hematopoietic stem cells. Moreover, knockdown of JAM3 leads to a dramatic decrease in the proliferation of both human leukemia cell lines and primary LICs. JAM3 directly associates with LRP5 to activate the downstream PDK1/AKT pathway, followed by the downregulation of GSK3β and activation of β-catenin/CCND1 signaling, to maintain the self-renewal ability and cell cycle entry of LICs. Thus, JAM3 may serve as a functional LIC marker and play an important role in the maintenance of LIC stemness through unexpected LRP5/PDK1/AKT/GSK3β/β-catenin/CCND1 signaling pathways but not via its canonical role in cell junctions and migration. JAM3 may be an ideal therapeutic target for the eradication of LICs without influencing normal hematopoiesis.

Original languageEnglish (US)
Pages (from-to)1737-1751
Number of pages15
JournalJournal of Clinical Investigation
Volume128
Issue number5
DOIs
StatePublished - May 1 2018

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Junctional Adhesion Molecule C
Catenins
Leukemia
Cell Self Renewal
Intercellular Junctions
Hematopoiesis

ASJC Scopus subject areas

  • Medicine(all)

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JAM3 maintains leukemia-initiating cell self-renewal through LRP5/AKT/β-catenin/CCND1 signaling. / Zhang, Yaping; Xia, Fangzhen; Liu, Xiaoye; Yu, Zhuo; Xie, Li; Liu, Ligen; Chen, Chiqi; Jiang, Haishan; Hao, Xiaoxin; He, Xiaoxiao; Zhang, Feifei; Gu, Hao; Zhu, Jun; Bai, Haitao; Zhang, Chengcheng; Chen, Guo Qiang; Zheng, Junke.

In: Journal of Clinical Investigation, Vol. 128, No. 5, 01.05.2018, p. 1737-1751.

Research output: Contribution to journalArticle

Zhang, Y, Xia, F, Liu, X, Yu, Z, Xie, L, Liu, L, Chen, C, Jiang, H, Hao, X, He, X, Zhang, F, Gu, H, Zhu, J, Bai, H, Zhang, C, Chen, GQ & Zheng, J 2018, 'JAM3 maintains leukemia-initiating cell self-renewal through LRP5/AKT/β-catenin/CCND1 signaling', Journal of Clinical Investigation, vol. 128, no. 5, pp. 1737-1751. https://doi.org/10.1172/JCI93198
Zhang, Yaping ; Xia, Fangzhen ; Liu, Xiaoye ; Yu, Zhuo ; Xie, Li ; Liu, Ligen ; Chen, Chiqi ; Jiang, Haishan ; Hao, Xiaoxin ; He, Xiaoxiao ; Zhang, Feifei ; Gu, Hao ; Zhu, Jun ; Bai, Haitao ; Zhang, Chengcheng ; Chen, Guo Qiang ; Zheng, Junke. / JAM3 maintains leukemia-initiating cell self-renewal through LRP5/AKT/β-catenin/CCND1 signaling. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 5. pp. 1737-1751.
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abstract = "Leukemia-initiating cells (LICs) are responsible for the initiation, development, and relapse of leukemia. The identification of novel therapeutic LIC targets is critical to curing leukemia. In this report, we reveal that junctional adhesion molecule 3 (JAM3) is highly enriched in both mouse and human LICs. Leukemogenesis is almost completely abrogated upon Jam3 deletion during serial transplantations in an MLL-AF9-induced murine acute myeloid leukemia model. In contrast, Jam3 deletion does not affect the functions of mouse hematopoietic stem cells. Moreover, knockdown of JAM3 leads to a dramatic decrease in the proliferation of both human leukemia cell lines and primary LICs. JAM3 directly associates with LRP5 to activate the downstream PDK1/AKT pathway, followed by the downregulation of GSK3β and activation of β-catenin/CCND1 signaling, to maintain the self-renewal ability and cell cycle entry of LICs. Thus, JAM3 may serve as a functional LIC marker and play an important role in the maintenance of LIC stemness through unexpected LRP5/PDK1/AKT/GSK3β/β-catenin/CCND1 signaling pathways but not via its canonical role in cell junctions and migration. JAM3 may be an ideal therapeutic target for the eradication of LICs without influencing normal hematopoiesis.",
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AU - Yu, Zhuo

AU - Xie, Li

AU - Liu, Ligen

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AU - Zhang, Feifei

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AU - Zhu, Jun

AU - Bai, Haitao

AU - Zhang, Chengcheng

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AU - Zheng, Junke

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