YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies,Cell

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YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies
Cell ( IF 45.5 ) Pub Date : 2024-12-17 , DOI: 10.1016/j.cell.2024.11.007
Zhenhua Chen ₁ , Chengwu Zeng ₂ , Lu Yang ₁ , Yuan Che ₁ , Meiling Chen ₃ , Lillian Sau ₁ , Bintao Wang ₁ , Keren Zhou ₁ , Yu Chen ₄ , Ying Qing ₁ , Chao Shen ₁ , Tingjian Zhang ₅ , Mark Wunderlich ₆ , Dong Wu ₁ , Wei Li ₁ , Kitty Wang ₁ , Keith Leung ₁ , Miao Sun ₇ , Tingting Tang ₁ , Xin He ₈ , Lianjun Zhang ₈ , Srividya Swaminathan ₉ , James C Mulloy ₆ , Markus Müschen ₁₀ , Huilin Huang ₁₁ , Hengyou Weng ₁₂ , Gang Xiao ₁₃ , Xiaolan Deng ₁ , Jianjun Chen ₁

Affiliation

Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Center for RNA Biology and Therapeutics, City of Hope Beckman Research Institute, Duarte, CA 91010, USA.
Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Center for RNA Biology and Therapeutics, City of Hope Beckman Research Institute, Duarte, CA 91010, USA; Jinan University Institute of Hematology, and Department of Hematology, The Fifth Affiliated Hospital Guangzhou Medical University, Guangzhou 510700, China.
Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Center for RNA Biology and Therapeutics, City of Hope Beckman Research Institute, Duarte, CA 91010, USA; Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China.
Molecular Instrumentation Center, University of California, Los Angeles, CA 90095, USA.
School of Pharmacy, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Keck School of Medicine, University of Southern California, and Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Department of Hematological Malignancies Translational Science, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Center of Molecular and Cellular Oncology, and Department of Immunobiology, Yale University, New Haven, CT 06511, USA.
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.
Guangzhou Laboratory, Guangzhou, Guangdong 510005, China.
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China.

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.

中文翻译：

YTHDF2 促进 B 细胞恶性肿瘤中的 ATP 合成和免疫逃逸

嵌合抗原受体（CAR）-T 细胞免疫治疗后 B 细胞恶性肿瘤患者的长期持久缓解仍然不令人满意，通常是由于抗原逃逸。恶性 B 细胞转化和致癌生长依赖于有效的 ATP 合成，但其潜在机制尚不清楚。在这里，我们报道了 YTHDF2 促进 B 细胞恶性肿瘤中的能量供应和抗原逃逸，仅其过表达就足以引起 B 细胞转化和肿瘤发生。从机制上讲，YTHDF2 起双读取器的作用，它通过募集 PABPC1 将 mRNA 稳定为 5-甲基胞嘧啶（m5C）读取器，从而增强它们的表达和 ATP 合成。同时，YTHDF2 还通过破坏其他 mRNA 作为 N6-甲基腺苷（m6A）读取器的稳定性来促进免疫逃避。YTHDF2 的小分子介导靶向抑制侵袭性 B 细胞恶性肿瘤，并使它们对 CAR-T 细胞疗法敏感。

更新日期：2024-12-17

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