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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 RHOA G17V to promote AITL in mice but the functional role of DNMT3A mutations in AITL remains unclear. Here, we report that DNMT3A R882H , the most common mutation of DNMT3A in AITL, accelerates the development of Tet2 -/- ; RHOA G17V 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 -/- ; RHOA G17V or DNMT3A R882H ; Tet2 -/- ; RHOA G17V 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., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)