DNMT3AR882Haccelerates angioimmunoblastic T-cell lymphoma in mice

DNA methylation-related genes, including TET2, IDH2, and DNMT3Aare 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 TET2loss cooperates with RHOAG17Vto promote AITL in mice but the functional role of DNMT3Amutations in AITL remains unclear. Here, we report that DNMT3AR882H, the most common mutation of DNMT3Ain AITL, accelerates the development of Tet2−/−; RHOAG17VAITL 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−/−; RHOAG17Vor DNMT3AR882H; Tet2−/−; RHOAG17Vhematopoietic stem and progenitor cells. These single-cell landscapes reveal that DNMT3Amutation 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 DNMT3Amutation in AITL and sheds light on the molecular mechanisms of this disease.