YTHDF2 promotes ATP synthesis and immune evasion in B cell

被引：7

作者：

Chen, Zhenhua ^{[1
,2
]}

Zeng, Chengwu ^{[1
,2
,3
,4
]}

Yang, Lu ^{[1
,2
]}

Che, Yuan

Chen, Meiling ^{[1
,2
,5
]}

Sau, Lillian ^{[1
,2
]}

Wang, Bintao ^{[1
,2
]}

Zhou, Keren ^{[1
,2
]}

Chen, Yu ^{[6
]}

Qing, Ying ^{[1
,2
]}

Shen, Chao ^{[1
,2
]}

Zhang, Tingjian

Wunderlich, Mark ^{[8
]}

Wu, Dong ^{[1
,2
]}

Li, Wei ^{[1
,2
]}

Wang, Kitty ^{[1
,2
]}

Leung, Keith

Sun, Miao ^{[9
,10
]}

Tang, Tingting ^{[1
,2
,7
]}

He, Xin ^{[11
]}

Zhang, Lianjun ^{[11
]}

Swaminathan, Srividya ^{[1
]}

Mulloy, James C. ^{[8
]}

Muschen, Markus ^{[12
,13
]}

Huang, Huilin ^{[14
]}

Weng, Hengyou ^{[15
]}

Xiao, Gang ^{[16
,17
]}

Deng, Xiaolan ^{[1
,2
]}

Chen, Jianjun ^{[1
,2
]}

机构：

[1] Beckman Res Inst City Hope, Dept Syst Biol, Duarte, CA 91010 USA

[2] Beckman Res Inst City Hope, Ctr RNA Biol & Therapeut, Duarte, CA 91010 USA

[3] Guangzhou Med Univ, Jinan Univ, Inst Hematol, Guangzhou 510700, Peoples R China

[4] Guangzhou Med Univ, Affiliated Hosp 5, Dept Hematol, Guangzhou 510700, Peoples R China

[5] Fujian Med Univ, Fujian Inst Hematol, Dept Hematol, Fujian Prov Key Lab Hematol,Union Hosp, Fuzhou 350001, Fujian, Peoples R China

[6] Univ Calif Los Angeles, Mol Instrumentat Ctr, Los Angeles, CA 90095 USA

[7] China Med Univ, Sch Pharm, 77 Puhe Rd,North New Area, Shenyang 110122, Peoples R China

[8] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

[9] Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90027 USA

[10] Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90027 USA

[11] City Hope Natl Med Ctr, Beckman Res Inst, Dept Hematol Malignancies Translat Sci, Duarte, CA 91010 USA

[12] Yale Univ, Ctr Mol & Cellular Oncol, New Haven, CT 06511 USA

[13] Yale Univ, Dept Immunobiol, New Haven, CT 06511 USA

[14] Sun Yat Sen Univ, Guangdong Prov Clin Res Ctr Canc, Canc Ctr, Canc Ctr, Guangzhou 510060, Guangdong, Peoples R China

[15] Guangzhou Lab, Guangzhou 510005, Guangdong, Peoples R China

[16] Zhejiang Univ, Inst Immunol, Sch Med, Hangzhou 310058, Peoples R China

[17] Zhejiang Univ, Liangzhu Lab, Hangzhou 311121, Peoples R China

来源：

CELL | 2025年 / 188卷 / 02期

基金：

美国国家卫生研究院;

关键词：

MESSENGER-RNA STABILITY; OXIDATIVE-PHOSPHORYLATION; KAPPA-B; CANCER; LEUKEMIA; IDENTIFICATION; LYMPHOMAS; THERAPY; COMPLEX; TARGET;

D O I：

10.1016/j.cell.2024.11.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Long-term durable remission in patients with B cell malignancies following chimeric antigen receptor (CAR)-T cell immunotherapy remains unsatisfactory, often due to antigen escape. Malignant B cell transformation and oncogenic growth relies on efficient ATP synthesis, although the underlying mechanisms remain unclear. Here, we report that YTHDF2 facilitates energy supply and antigen escape in B cell malignancies, and its overexpression alone is sufficient to cause B cell transformation and tumorigenesis. Mechanistically, YTHDF2 functions as a dual reader where it stabilizes mRNAs as a 5-methylcytosine (m5C) reader via recruiting PABPC1, thereby enhancing their expression and ATP synthesis. Concomitantly, YTHDF2 also promotes immune evasion by destabilizing other mRNAs as an N6-methyladenosine (m6A) reader. Small-molecule- mediated targeting of YTHDF2 suppresses aggressive B cell malignancies and sensitizes them to CAR-T cell therapy.

引用

页码：331 / 351.e30

页数：52

共 115 条

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