Inactivating mutations in the acetyltransferase genes CREBBP and EP300 are frequently found in B-cell non-Hodgkin's lymphoma (B-NHL), including follicular lymphoma and diffuse large B-cell lymphoma (DLBCL). These mutations lead to reduced acetyltransferase activity, which affects the acetylation of key proteins such as BCL6 and p53. BCL6 is a transcriptional repressor that, when acetylated, is inactivated, while p53 is a tumor suppressor that requires acetylation for its transcriptional activity. The loss of these functions contributes to lymphomagenesis by promoting the survival and proliferation of malignant B cells. CREBBP and EP300 are histone and non-histone acetyltransferases that function as transcriptional coactivators in multiple signaling pathways. Mutations in these genes are associated with reduced expression of the proteins, leading to impaired acetylation of BCL6 and p53. These mutations are predominantly monoallelic, affecting one allele, and are more common in GCB-DLBCL than in ABC-DLBCL. In follicular lymphoma, similar mutations are also observed, suggesting a shared pathogenic mechanism in these B-cell malignancies. The study highlights the importance of CREBBP and EP300 in the pathogenesis of B-NHL, with their inactivation contributing to the development of these cancers. The findings suggest that targeting acetylation/deacetylation mechanisms could be a promising therapeutic approach for B-NHL. The results also indicate that additional epigenetic mechanisms may contribute to the reduction of HAT dosage in a larger fraction of tumors. Overall, the study provides important insights into the molecular mechanisms underlying B-NHL and highlights the potential of acetylation-targeting therapies in the treatment of these cancers.Inactivating mutations in the acetyltransferase genes CREBBP and EP300 are frequently found in B-cell non-Hodgkin's lymphoma (B-NHL), including follicular lymphoma and diffuse large B-cell lymphoma (DLBCL). These mutations lead to reduced acetyltransferase activity, which affects the acetylation of key proteins such as BCL6 and p53. BCL6 is a transcriptional repressor that, when acetylated, is inactivated, while p53 is a tumor suppressor that requires acetylation for its transcriptional activity. The loss of these functions contributes to lymphomagenesis by promoting the survival and proliferation of malignant B cells. CREBBP and EP300 are histone and non-histone acetyltransferases that function as transcriptional coactivators in multiple signaling pathways. Mutations in these genes are associated with reduced expression of the proteins, leading to impaired acetylation of BCL6 and p53. These mutations are predominantly monoallelic, affecting one allele, and are more common in GCB-DLBCL than in ABC-DLBCL. In follicular lymphoma, similar mutations are also observed, suggesting a shared pathogenic mechanism in these B-cell malignancies. The study highlights the importance of CREBBP and EP300 in the pathogenesis of B-NHL, with their inactivation contributing to the development of these cancers. The findings suggest that targeting acetylation/deacetylation mechanisms could be a promising therapeutic approach for B-NHL. The results also indicate that additional epigenetic mechanisms may contribute to the reduction of HAT dosage in a larger fraction of tumors. Overall, the study provides important insights into the molecular mechanisms underlying B-NHL and highlights the potential of acetylation-targeting therapies in the treatment of these cancers.