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DNMT3AR882H accelerates angioimmunoblastic T-cell lymphoma in mice

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Abstract

DNA methylation-related genes, including TET2, IDH2, and DNMT3A are highly frequently mutated in angioimmunoblastic T-cell lymphoma (AITL), an aggressive malignancy of T follicular helper (Tfh) cells associated with aberrant immune features. It has been shown that TET2 loss cooperates with RHOAG17V to promote AITL in mice but the functional role of DNMT3A mutations in AITL remains unclear. Here, we report that DNMT3AR882H, the most common mutation of DNMT3A in AITL, accelerates the development of Tet2−/−; RHOAG17V AITL in mice, indicated by the expansion of malignant Tfh cells and aberrant B cells, skin rash, and significantly shortened disease-free survival. To understand the underlying cellular and molecular mechanisms, we performed single-cell transcriptome analyses of lymph nodes of mice transplanted with Tet2−/−, Tet2−/−; RHOAG17V or DNMT3AR882H; Tet2−/−; RHOAG17V hematopoietic stem and progenitor cells. These single-cell landscapes reveal that DNMT3A mutation further activates Tfh cells and leads to rapid and terminal differentiation of B cells, probably through enhancing the interacting PD1/PD-L1, ICOS/ICOSL, CD28/CD86, and ICAM1/ITGAL pairs. Our study establishes the functional roles of DNMT3A mutation in AITL and sheds light on the molecular mechanisms of this disease.

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Fig. 1: DNMT3A alterations frequently happen in human AITL.
Fig. 2: DNMT3AR882H accelerates AITL formation in mice.
Fig. 3: DNMT3AR882H promotes the pathologic features of AITL.
Fig. 4: The single-cell transcriptome analyses of mouse AITL.
Fig. 5: DNMT3A R882H promotes the activation of Tfh cells.
Fig. 6: Enhanced B cell differentiation and maturation in AITL mice with DNMT3A mutation.

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Data availability

Single-cell RNA-seq data were deposited in the Gene Expression Omnibus database repository under accession number 142645. The private code of GSE142645 is mfuvgkuerburdqr.

Code availability

The analysis code can be found on GitHub (https://github.com/pangxueyu233/DNMT3AR882H-accelerates-angioimmunoblastic-T-cell-lymphoma).

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Acknowledgements

We thank all the members of the Chen and Liu laboratory for their invaluable suggestions and technical support. We thank Dr. Yuquan Wei for his generous support. We thank Dr. Renzhan Tong for his technical support. We thank the Core Facilities of West China Hospital for technical support.

Funding

This work was supported by the National Natural Science Foundation of China (82130007), the Sichuan Science and Technology Program (2018RZ0140, 2018JZ0077, 2022YFS0205), the Incubation Program for Clinical Trials (19HXFH030), the Achievement Transformation Project (CGZH21001), the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYJC21009, ZYGD22012, ZYJC21007), and the Translational Research Grant of NCRCH (2021WWB03).

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Author notes

  1. These authors contributed equally: Jianan Zheng, Zhongwang Wang, Xiangyu Pan.

Authors and Affiliations

  1. Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    Jianan Zheng, Xiangyu Pan, Xintong Deng, Pengpeng Liu, Qi Zhang, Chong Chen & Yu Liu

  2. Department of Hematology, West China Hospital, Sichuan University, Chengdu, China

    Zhongwang Wang, He Li & Ting Niu

  3. Department of Technology, Chengdu ExAb Biotechnology, LTD, Chengdu, China

    Zhixin Zhang

  4. Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

    Feifei Na

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  1. Jianan Zheng
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Contributions

CC and YL conceived the project and designed experiments. ZW, JZ, ZZ, HL, PL, QZ, XD and FN performed experiments. XP performed bioinformatic analyses. ZW, JZ, XP, CC, TN and YL analyzed data. ZW, JZ, XP, TN and YL prepared and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ting Niu or Yu Liu.

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Zheng, J., Wang, Z., Pan, X. et al. DNMT3AR882H accelerates angioimmunoblastic T-cell lymphoma in mice. Oncogene 42, 1940–1950 (2023). https://doi.org/10.1038/s41388-023-02699-2

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