YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2024-12-17 DOI:10.1016/j.cell.2024.11.007

Zhenhua Chen, Chengwu Zeng, Lu Yang, Yuan Che, Meiling Chen, Lillian Sau, Bintao Wang, Keren Zhou, Yu Chen, Ying Qing, Chao Shen, Tingjian Zhang, Mark Wunderlich, Dong Wu, Wei Li, Kitty Wang, Keith Leung, Miao Sun, Tingting Tang, Xin He, Jianjun Chen

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引用次数: 0

Abstract

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.

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.