Mutant NPM1-Regulated FTO-Mediated m(6)A Demethylation Promotes Leukemic Cell Survival via PDGFRB/ERK Signaling Axis

作者全名："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"

作者地址："[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; Zhang, Ling] Chongqing Med Univ, Sch Lab Med, Key Lab Lab Med Diagnost Designated, Minist Educ, Chongqing, Peoples R China; [Yang, Zailin] Chongqing Univ, Hematol Oncol Ctr, Canc Hosp, Chongqing, Peoples R China"

通信作者："Zhang, L (通讯作者)，Chongqing Med Univ, Sch Lab Med, Key Lab Lab Med Diagnost Designated, Minist Educ, Chongqing, Peoples R China."

来源：FRONTIERS IN ONCOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000760634300001

JCR分区：Q2

影响因子：4.7

年份：2022

卷号：12

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：acute myeloid leukemia; nucleophosmin 1; N-6-methyladenosine; FTO; PDGFRB; ERK cascade

摘要："Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations exhibits distinct biological and clinical features, accounting for approximately one-third of AML. Recently, the N-6-methyladenosine (m(6)A) RNA modification has emerged as a new epigenetic modification to contribute to tumorigenesis and development. However, there is limited knowledge on the role of m(6)A modifications in NPM1-mutated AML. In this study, the decreased m(6)A level was first detected and high expression of fat mass and obesity-associated protein (FTO) was responsible for the m(6)A 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 m(6)A RNA demethylase activity to activate PDGFRB/ERK signaling axis. Our findings indicate that FTO-mediated m(6)A 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."

基金机构："National Natural Science Foundation of China [NSFC81873973, NSFC82072353]; Natural Science Foundation of CQ CSTC [cstc2019jcyj-msxmX0229, cstc2021jcyj-msxmX0363]"

基金资助正文：Funding This work was supported by the National Natural Science Foundation of China (NSFC81873973 and NSFC82072353) and the Natural Science Foundation of CQ CSTC (cstc2019jcyj-msxmX0229 and cstc2021jcyj-msxmX0363).