髓系白血病
重编程
白血病
泛素连接酶
生物
泛素
调节器
细胞生物学
癌症研究
化学
生物化学
细胞
免疫学
基因
作者
Shinichiro Matsui,Chihiro Ri,Lyndsey Bolanos,Kwangmin Choi,Asuka Shibamiya,Arata Ishii,Koji Takaishi,Nagisa Oshima-Hasegawa,Shokichi Tsukamoto,Yusuke Takeda,Naoya Mimura,Akihide Yoshimi,Koutaro Yokote,Daniel T. Starczynowski,Emiko Sakaida,Tomoya Muto
出处
期刊:Leukemia
[Springer Nature]
日期:2024-04-12
标识
DOI:10.1038/s41375-024-02245-3
摘要
Abstract TNF receptor associated factor 6 (TRAF6) is an E3 ubiquitin ligase that has been implicated in myeloid malignancies. Although altered TRAF6 expression is observed in human acute myeloid leukemia (AML), its role in the AML pathogenesis remains elusive. In this study, we showed that the loss of TRAF6 in AML cells significantly impairs leukemic function in vitro and in vivo, indicating its functional importance in AML subsets. Loss of TRAF6 induces metabolic alterations, such as changes in glycolysis, TCA cycle, and nucleic acid metabolism as well as impaired mitochondrial membrane potential and respiratory capacity. In leukemic cells, TRAF6 expression shows a positive correlation with the expression of O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT), which catalyzes the addition of O-GlcNAc to target proteins involved in metabolic regulation. The restoration of growth capacity and metabolic activity in leukemic cells with TRAF6 loss, achieved through either forced expression of OGT or pharmacological inhibition of O-GlcNAcase (OGA) that removes O-GlcNAc, indicates the significant role of O-GlcNAc modification in the TRAF6-related cellular and metabolic dynamics. Our findings highlight the oncogenic function of TRAF6 in leukemia and illuminate the novel TRAF6/OGT/O-GlcNAc axis as a potential regulator of metabolic reprogramming in leukemogenesis.
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