CREBBP mutation promotes tumor growth and CD8+ T-cell dysfunction in DLBCL via NOTCH-STAT1-LGALS9 signaling

Abstract Epigenetic reprogramming is increasingly recognized as a key driver of clonal evolution and therapeutic resistance in diffuse large B-cell lymphoma (DLBCL), yet how epigenetic mutations shape the tumor microenvironment (TME) remains unclear. Here we investigated the recurrent CREB binding protein (CREBBP) Y1503C mutation, which is frequently mutated in DLBCL. Biomedical, enzymatic and computational analysis showed that this mutant loses its acetyltransferase activity toward H3K18 and H3K27 due to structural destabilization and conformational alteration compared to the wild-type (WT) protein. Mechanistically, loss-of-function mutation of CREBBP reduces the expression of FBXW7, resulting in sustained activation of NOTCH signaling that promotes tumor growth and impairs CD8 + T cell activation. Analysis of tumor-immune cell communication further revealed that CREBBP mutant-driven NOTCH activation in malignant B cells increases STAT1-dependent LGALS9 expression, which engages TIM3 and PD-1 on CD8 + exhausted T cells, contributing to immunosuppressive TME. Collectively, these findings indicate that the CREBBP Y1503C mutation not only promotes DLBCL cell growth but also drives CD8 + T-cell dysfunction. These results support targeting the NOTCH-STAT1-LGALS9 axis to overcome epigenetically mediated immune evasion and tumor development.