Decoding m6A RNA methylome identifies PRMT6-regulated lipid transport promoting AML stem cell maintenance

被引：37

作者：

Cheng, Ying ^{[1
,2
,3
]}

Gao, Zhuying ^{[1
,2
,3
]}

Zhang, Tiantian ^{[1
,2
,3
]}

Wang, Yuhua ^{[1
,2
]}

Xie, Xueqin ^{[3
]}

Han, Guoqiang ^{[3
]}

Li, Yashu ^{[3
]}

Yin, Rong ^{[4
]}

Chen, Yilin

Wang, Peipei ^{[3
]}

Hu, Jin ^{[3
]}

Zhang, Tong

Guo, Chengli ^{[1
,2
]}

Chai, Jihua ^{[1
,2
]}

Wang, Jing ^{[1
,2
]}

Cui, Manman ^{[3
]}

Gao, Kexin ^{[3
]}

Liu, Weidong ^{[1
,2
]}

Yao, Shuxin ^{[3
]}

Lu, Pengbo ^{[3
]}

Cao, Ziyan ^{[3
]}

Zheng, Yanbing ^{[3
]}

Chang, Jiwei ^{[1
,2
]}

Liu, Zheming ^{[6
]}

Song, Qibin ^{[6
]}

Li, Weiming ^{[5
]}

Zhou, Fuling ^{[4
]}

Zhang, Haojian ^{[1
,2
,3
,7
]}

机构：

[1] Wuhan Univ, Med Res Inst, Sch & Hosp Stomatol, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan, Peoples R China

[2] Wuhan Univ, Med Res Inst, Sch & Hosp Stomatol, Key Lab Oral Biomed Minist Educ, Wuhan, Peoples R China

[3] Wuhan Univ, Frontier Sci Ctr Immunol & Metab, Wuhan, Peoples R China

[4] Wuhan Univ, Zhongnan Hosp, Dept Hematol, Wuhan, Peoples R China

[5] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Hematol, Wuhan, Peoples R China

[6] Wuhan Univ, Renmin Hosp, Ctr Canc, Wuhan, Peoples R China

[7] Wuhan Univ, Taikang Ctr Life & Med Sci, Wuhan, Peoples R China

来源：

CELL STEM CELL | 2023年 / 30卷 / 01期

基金：

国家重点研发计划; 中国国家自然科学基金; 中国博士后科学基金;

关键词：

ACUTE MYELOID-LEUKEMIA; MESSENGER-RNA; HEMATOPOIETIC STEM; NUCLEAR-RNA; METHYLATION; DIFFERENTIATION; METABOLISM; MFSD2A; N-6-METHYLADENOSINE; LEUKEMOGENESIS;

D O I：

10.1016/j.stem.2022.12.003

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

N-6-methyladenosine (m(6)A) is a common chemical modification for mammalian mRNA and exhibits high dynamics in various biological processes. However, dynamics of m(6)A RNA methylome during leukemogenesis remains unknown. Here, we delineate a comprehensive m(6)A landscape during acute myeloid leukemia (AML) development and identify PRMT6 as a key for maintaining AML stem cells. We observe an obvious change in m(6)A methylome during leukemogenesis and find that protein arginine methyltransferase PRMT6 and m(6)A reader IGF2BP2 maintain the function of human and murine leukemia stem cells (LSCs). Genetic deletion or pharmacological inhibition of PRMT6 damages AML development and LSC function. Mechanistically, IGF2BP2 stabilizes PRMT6 mRNA via m(6)A-mediated manner, which catalyzes H3R2me2a and suppresses lipid transporter MFSD2A expression. PRMT6 loss upregulates MFSD2A expression that increases docosahexaenoic acid levels and impairs LSC maintenance. Collectively, our findings reveal a critical role of PRMT6-MFSD2A signaling axis in AML development and provide a therapeutic strategy for targeting LSCs.

引用

页码：69 / +

页数：24

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