CREBBP, also known as CREB-binding protein, is a lysine acetyltransferase belonging to the KAT3 family. It modifies histones and non-histone proteins, regulating chromatin accessibility and transcription. It is involved in DNA replication, DNA repair processes such as base excision repair, nucleotide excision repair, and non-homologous end-joining, and also in DNA damage signaling pathways [2].

In diffuse large B-cell lymphoma (DLBCL), CREBBP mutations occur in 8.4% of patients. Mutations or knockdown of CREBBP in B-lymphoma cells inhibit H3K27 acetylation, downregulate FBXW7 expression, activate the NOTCH pathway and downstream CCL2/CSF1 expression. This leads to tumor-associated macrophage polarization to the M2 phenotype and tumor cell proliferation. In B-lymphoma murine models, xenografted tumors with CREBBP mutations have lower H3K27 acetylation, higher M2 macrophage recruitment, and more rapid tumor growth via the FBXW7-NOTCH-CCL2/CSF1 axis [1]. In addition, in B-cell malignancies, CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Co-targeting CREBBP and AURKA suppresses MYC transcriptionally and post-translationally to induce replication stress and apoptosis, and in vivo studies show that AURKA inhibition is efficacious in delaying tumor progression in CREBBP-deficient cells [3].

In conclusion, CREBBP is crucial for regulating chromatin-related functions and gene expression. Studies using gene-knockout models in B-cell malignancies, especially DLBCL, have revealed its role in tumor-associated macrophage polarization and tumor growth. These findings provide insights into the mechanisms of disease development and potential therapeutic targets for B-cell malignancies.