YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies

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

doi:10.1016/j.cell.2024.11.007

YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies

Cell. 2025 Jan 23;188(2):331-351.e30. doi: 10.1016/j.cell.2024.11.007. Epub 2024 Dec 17.

Authors

Zhenhua Chen¹, Chengwu Zeng², Lu Yang³, Yuan Che³, Meiling Chen⁴, Lillian Sau³, Bintao Wang³, Keren Zhou³, Yu Chen⁵, Ying Qing³, Chao Shen³, Tingjian Zhang⁶, Mark Wunderlich⁷, Dong Wu³, Wei Li³, Kitty Wang³, Keith Leung³, Miao Sun⁸, Tingting Tang³, Xin He⁹, Lianjun Zhang⁹, Srividya Swaminathan¹⁰, James C Mulloy⁷, Markus Müschen¹¹, Huilin Huang¹², Hengyou Weng¹³, Gang Xiao¹⁴, Xiaolan Deng¹⁵, Jianjun Chen¹⁶

Affiliations

¹ 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. Electronic address: zhenhchen@coh.org.
² 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.
³ 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.
⁴ 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.
⁵ Molecular Instrumentation Center, University of California, Los Angeles, CA 90095, USA.
⁶ School of Pharmacy, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China.
⁷ Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁸ 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.
⁹ Department of Hematological Malignancies Translational Science, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
¹⁰ Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
¹¹ Center of Molecular and Cellular Oncology, and Department of Immunobiology, Yale University, New Haven, CT 06511, USA.
¹² 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.
¹³ Guangzhou Laboratory, Guangzhou, Guangdong 510005, China.
¹⁴ Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China.
¹⁵ 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. Electronic address: xideng@coh.org.
¹⁶ 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. Electronic address: jianchen@coh.org.

PMID: 39694037
PMCID: PMC12394000 (available on 2026-01-23)
DOI: 10.1016/j.cell.2024.11.007

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.

Keywords: ATP production; B cell malignancies; CAR-T; CD19; MHC-II; YTHDF2; m(5)C; m(6)A; metabolism.

MeSH terms

5-Methylcytosine / metabolism
Adenosine / analogs & derivatives
Adenosine Triphosphate* / biosynthesis
Adenosine Triphosphate* / metabolism
Animals
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
Cell Line, Tumor
Cell Transformation, Neoplastic
Humans
Immune Evasion*
Immunotherapy, Adoptive
Mice
RNA, Messenger / metabolism
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism
Receptors, Chimeric Antigen / metabolism

Substances

Adenosine Triphosphate
RNA-Binding Proteins
YTHDF2 protein, human
N-methyladenosine
RNA, Messenger
5-Methylcytosine
Receptors, Chimeric Antigen
Adenosine

Abstract

MeSH terms

Substances

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