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

• Published in: Cell stem cell Vol. 30; no. 1; pp. 69 - 85.e7
• Main Authors: Cheng, Ying, Gao, Zhuying, Zhang, Tiantian, Wang, Yuhua, Xie, Xueqin, Han, Guoqiang, Li, Yashu, Yin, Rong, Chen, Yilin, Wang, Peipei, Hu, Jin, Zhang, Tong, Guo, Chengli, Chai, Jihua, Wang, Jing, Cui, Manman, Gao, Kexin, Liu, Weidong, Yao, Shuxin, Lu, Pengbo, Cao, Ziyan, Zheng, Yanbing, Chang, Jiwei, Liu, Zheming, Song, Qibin, Li, Weiming, Zhou, Fuling, Zhang, Haojian
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 05.01.2023
• Subjects: acute myeloid leukemia; IGF2BP2; leukemia stem cells; PRMT6; RNA m6A; RNA m6A; PRMT6; leukemia stem cells; IGF2BP2; acute myeloid leukemia
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2022.12.003

N6-methyladenosine (m6A) is a common chemical modification for mammalian mRNA and exhibits high dynamics in various biological processes. However, dynamics of m6A RNA methylome during leukemogenesis remains unknown. Here, we delineate a comprehensive m6A landscape during acute myeloid leukemia (AML) development and identify PRMT6 as a key for maintaining AML stem cells. We observe an obvious change in m6A methylome during leukemogenesis and find that protein arginine methyltransferase PRMT6 and m6A 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 m6A-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. [Display omitted] •A comprehensive m6A methylome in acute myeloid leukemia development is established•Loss of PRMT6 delays AML development and impairs leukemia stem cell function•PRMT6 is regulated by IGF2BP2 via stabilizing its mRNA in an m6A-dependent manner•PRMT6 installs H3R2me2a to inhibit MFSD2A expression that restrains DHA levels Cheng et al. delineate a comprehensive m6A landscape during acute myeloid leukemia (AML) development and identify PRMT6, regulated by IGF2BP2, acting as a key for leukemia stem cell maintenance by restraining MFSD2A expression and docosahexaenoic acid levels. These findings provide the rationale for targeting PRMT6-MFSD2A signaling axis in AML therapy.