Xiao Qiaoling, Lei Li, Ren Jun, Peng Meixi, Jing Yipei, Jiang Xueke, Huang Junpeng, Tao Yonghong, Lin Can, Yang Jing, Sun Minghui, Tang Lisha, Wei Xingyu, Yang Zailin, Zhang Ling
Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Hematology Oncology Center, Chongqing University Cancer Hospital, Chongqing, China.
Front Oncol. 2022 Feb 8;12:817584. doi: 10.3389/fonc.2022.817584. eCollection 2022.
Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations exhibits distinct biological and clinical features, accounting for approximately one-third of AML. Recently, the -methyladenosine (mA) RNA modification has emerged as a new epigenetic modification to contribute to tumorigenesis and development. However, there is limited knowledge on the role of mA modifications in NPM1-mutated AML. In this study, the decreased mA level was first detected and high expression of fat mass and obesity-associated protein (FTO) was responsible for the mA suppression in NPM1-mutated AML. FTO upregulation was partially induced by NPM1 mutation type A (NPM1-mA) through impeding the proteasome pathway. Importantly, FTO promoted leukemic cell survival by facilitating cell cycle and inhibiting cell apoptosis. Mechanistic investigations demonstrated that FTO depended on its mA RNA demethylase activity to activate PDGFRB/ERK signaling axis. Our findings indicate that FTO-mediated mA demethylation plays an oncogenic role in NPM1-mutated AML and provide a new layer of epigenetic insight for future treatments of this distinctly leukemic entity.
伴有核磷蛋白1（NPM1）突变的急性髓系白血病（AML）具有独特的生物学和临床特征，约占AML的三分之一。最近，N6-甲基腺苷（m6A）RNA修饰已成为一种新的表观遗传修饰，有助于肿瘤的发生和发展。然而，关于m6A修饰在NPM1突变型AML中的作用，人们了解有限。在本研究中，首次检测到m6A水平降低，且脂肪量和肥胖相关蛋白（FTO）的高表达是NPM1突变型AML中m6A受抑制的原因。NPM1 A型突变（NPM1-mA）通过阻碍蛋白酶体途径部分诱导了FTO上调。重要的是，FTO通过促进细胞周期进程和抑制细胞凋亡来促进白血病细胞存活。机制研究表明，FTO依赖其m6A RNA去甲基化酶活性来激活血小板衍生生长因子受体B（PDGFRB）/细胞外信号调节激酶（ERK）信号轴。我们的研究结果表明，FTO介导的m6A去甲基化在NPM1突变型AML中发挥致癌作用，并为这种独特白血病实体的未来治疗提供了新的表观遗传学见解。
