美国贝克曼希望之城研究所陈建军等研究人员合作发现，YTHDF2促进B细胞恶性肿瘤中的ATP合成和免疫逃逸。该项研究成果于2024年12月17日在线发表在《细胞》杂志上。
研究人员发现YTHDF2在B细胞恶性肿瘤中促进能量供应和抗原逃逸，其过表达本身足以引起B细胞转化和肿瘤发生。机制上，YTHDF2作为双重阅读因子发挥作用，通过招募PABPC1作为5-甲基胞嘧啶（m5C）读取因子，稳定mRNA，从而增强其表达和ATP合成。
同时，YTHDF2也通过作为N6-甲基腺苷（m6A）读取因子，破坏其他mRNA的稳定性，促进免疫逃逸。小分子靶向YTHDF2可抑制侵袭性B细胞恶性肿瘤，并增强其对嵌合抗原受体（CAR）T细胞治疗的敏感性。
研究人员表示，在接受CAR T细胞免疫疗法的B细胞恶性肿瘤患者中，长期耐药缓解仍不令人满意，这常常由于抗原逃逸。恶性B细胞转化和致癌生长依赖于高效的ATP合成，尽管其潜在机制尚不清楚。
附：英文原文
Title: YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies
Author: 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, Lianjun Zhang, Srividya Swaminathan, James C. Mulloy, Markus Müschen, Huilin Huang, Hengyou Weng, Gang Xiao, Xiaolan Deng, Jianjun Chen
Issue&Volume: 2024-12-17
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.
DOI: 10.1016/j.cell.2024.11.007
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01324-2