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.

TNF 受体相关因子 6 (TRAF6) 是一种 E3 泛素连接酶，与骨髓恶性肿瘤有关。尽管在人类急性髓系白血病 (AML) 中观察到 TRAF6 表达发生改变，但其在 AML 发病机制中的作用仍然难以捉摸。在这项研究中，我们发现 AML 细胞中 TRAF6 的缺失会显着损害体外和体内的白血病功能，表明其在 AML 亚群中的功能重要性。 TRAF6 的缺失会引起代谢改变，例如糖酵解、TCA 循环和核酸代谢的变化以及线粒体膜电位和呼吸能力受损。在白血病细胞中，TRAF6 表达与 O-连接 N-乙酰氨基葡萄糖 (O-GlcNAc) 转移酶 (OGT) 的表达呈正相关，OGT 催化 O-GlcNAc 添加到参与代谢调节的靶蛋白上。通过强制表达 OGT 或药理抑制去除 O-GlcNAc 的 O-GlcNAcase (OGA)，TRAF6 缺失的白血病细胞恢复生长能力和代谢活性，表明 O-GlcNAc 修饰在 TRAF6 中的重要作用-相关的细胞和代谢动力学。我们的研究结果强调了 TRAF6 在白血病中的致癌功能，并阐明了新型 TRAF6/OGT/O-GlcNAc 轴作为白血病发生中代谢重编程的潜在调节剂。