Targeting PRMT1 prevents acute and chronic graft-versus-host disease

• Published in: Molecular therapy 2023-11, Vol.31 (11), p.3259-3276
• Main Authors: Zhao, Xiaoyan, Sun, Yan, Xu, Ziwei, Cai, Li, Hu, Yu, Wang, Huafang
• Format: Article
• Language: English
• Subjects: allogeneic hematopoietic stem cell transplantation; Animals; B cells; B-Lymphocytes; Bronchiolitis Obliterans Syndrome; Graft vs Host Disease - genetics; Graft vs Host Disease - prevention & control; graft-versus-host disease; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; IDH2; Methyltransferases; Mice; Original; Plasma Cells; PRMT1; Protein-Arginine N-Methyltransferases - genetics; Repressor Proteins - genetics; T cells
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2023.09.011

Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Recent studies have reported that protein arginine methyltransferase 1 (PRMT1) is essential for the differentiation and proliferation of T and B cells. Therefore, it is possible that PRMT1 may play a critical role in GVHD. In this study, we observed that PRMT1 expression was upregulated in CD4+ T and B cells from chronic GVHD (cGVHD) patients and mice. However, the prophylactic use of a PRMT1 inhibitor significantly prevented cGVHD in mice by reducing the percentage of T helper (Th)17 cells, germinal center B cells, and plasma cells. The PRMT1 inhibitor also controlled acute GVHD (aGVHD) in mice by decreasing the percentage of Th17 cells. Moreover, inhibiting PRMT1 also weakened Th17 cell differentiation, B cell proliferation, and antibody production in cells from cGVHD patients. Additionally, further studies revealed that PRMT1 regulated B cell proliferation and antibody secretion by methylating isocitrate dehydrogenase 2 (IDH2). We observed asymmetric di-methylation of IDH2 by PRMT1 at arginine 353 promoted IDH2 homodimerization, which enhanced IDH2 activity, further increasing B cell proliferation and antibody production. Collectively, this study provides a rationale for the application of PRMT1 inhibitors in the prevention of aGVHD and cGVHD. [Display omitted] HF Wang and colleagues reveal inhibiting PRMT1 can prevent GVHD. Furthermore, they find that PRMT1 promotes IDH2 homodimerization and activity by methylating IDH2 at arginine-353, which can induce B cell proliferation and antibody secretion, thereby leading to chronic GVHD.