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

被引：29

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

共 56 条

[1] [Anonymous], 2012, HEALTH-LONDON, V126, P967, DOI [10.1016/j.puhe.2012.07.004, DOI 10.1016/J.PUHE.2012.07.004]
[2] Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control
Barbieri, Isaia
Tzelepis, Konstantinos
Pandolfini, Luca
Shi, Junwei
Millan-Zambrano, Gonzalo
Robson, Samuel C.
Aspris, Demetrios
Migliori, Valentina
Bannister, Andrew J.
Han, Namshik
De Braekeleer, Etienne
Ponstingl, Hannes
Hendrick, Alan
Vakoc, Christopher R.
Vassiliou, George S.
Kouzarides, Tony
[J]. NATURE, 2017, 552 (7683) : 126 - +
[3] Mfsd2a is critical for the formation and function of the blood-brain barrier
Ben-Zvi, Ayal
Lacoste, Baptiste
Kur, Esther
Andreone, Benjamin J.
Mayshar, Yoav
Yan, Han
Gu, Chenghua
[J]. NATURE, 2014, 509 (7501) : 507 - +
[4] Biological roles of adenine methylation in RNA
Boulias, Konstantinos
Greer, Eric Lieberman
[J]. NATURE REVIEWS GENETICS, 2023, 24 (03) : 143 - 160
[5] Bresciani Guilherme, 2005, P NATL ACAD SCI, V80, P1, DOI [10.1016/j.ijdevneu.2014.05.007, DOI 10.1111/1469-8986.3720163, 10.1016/j.nutres.2020.05.005, DOI 10.1073/PNAS.0506580102]
[6] m6A RNA Methylation Maintains Hematopoietic Stem Cell Identity and Symmetric Commitment
Cheng, Yuanming
Luo, Hanzhi
Izzo, Franco
Pickering, Brian F.
Diu Nguyen
Myers, Robert
Schurer, Alexandra
Gourkanti, Saroj
Bruening, Jens C.
Vu, Ly P.
Jaffrey, Samie R.
Landau, Dan A.
Kharas, Michael G.
[J]. CELL REPORTS, 2019, 28 (07): : 1703 - +
[7] IDENTIFICATION OF METHYLATED NUCLEOSIDES IN MESSENGER-RNA FROM NOVIKOFF HEPATOMA-CELLS
DESROSIERS, R
FRIDERICI, K
ROTTMAN, F
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1974, 71 (10) : 3971 - 3975
[8] Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq
Dominissini, Dan
Moshitch-Moshkovitz, Sharon
Schwartz, Schraga
Salmon-Divon, Mali
Ungar, Lior
Osenberg, Sivan
Cesarkas, Karen
Jacob-Hirsch, Jasmine
Amariglio, Ninette
Kupiec, Martin
Sorek, Rotem
Rechavi, Gideon
[J]. NATURE, 2012, 485 (7397) : 201 - U84
[9] Stem cell gene expression programs influence clinical outcome in human leukemia
Eppert, Kolja
Takenaka, Katsuto
Lechman, Eric R.
Waldron, Levi
Nilsson, Bjoern
van Galen, Peter
Metzeler, Klaus H.
Poeppl, Armando
Ling, Vicki
Beyene, Joseph
Canty, Angelo J.
Danska, Jayne S.
Bohlander, Stefan K.
Buske, Christian
Minden, Mark D.
Golub, Todd R.
Jurisica, Igor
Ebert, Benjamin L.
Dick, John E.
[J]. NATURE MEDICINE, 2011, 17 (09) : 1086 - U91
[10] YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner
Feng, Mengdie
Xie, Xueqin
Han, Guoqiang
Zhang, Tiantian
Li, Yashu
Li, Yicun
Yin, Rong
Wang, Qifan
Zhang, Tong
Wang, Peipei
Hu, Jin
Cheng, Ying
Gao, Zhuying
Wang, Jing
Chang, Jiwei
Cui, Manman
Gao, Kexin
Chai, Jihua
Liu, Weidong
Guo, Chengli
Li, Shaoguang
Liu, Lingbo
Zhou, Fuling
Chen, Jianjun
Zhang, Haojian
[J]. BLOOD, 2021, 138 (01) : 71 - 85

← 1 2 3 4 5 6 →