CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis

Abstract

Epigenetic alterations play an important role in tumor progression of diffuse large B-cell lymphoma (DLBCL). However, the biological relevance of epigenetic gene mutations on tumor microenvironment remains to be determined. The core set of genes relating to histone methylation (KMT2D, KMT2C, EZH2), histone acetylation (CREBBP, EP300), DNA methylation (TET2), and chromatin remodeling (ARID1A) were detected in the training cohort of 316 patients by whole-genome/exome sequencing (WGS/WES) and in the validation cohort of 303 patients with newly diagnosed DLBCL by targeted sequencing. Their correlation with peripheral blood immune cells and clinical outcomes were assessed. Underlying mechanisms on tumor microenvironment were investigated both in vitro and in vivo. Among all 619 DLBCL patients, somatic mutations in KMT2D (19.5%) were most frequently observed, followed by mutations in ARID1A (8.7%), CREBBP (8.4%), KMT2C (8.2%), TET2 (7.8%), EP300 (6.8%), and EZH2 (2.9%). Among them, CREBBP/EP300 mutations were significantly associated with decreased peripheral blood absolute lymphocyte-to-monocyte ratios, as well as inferior progression-free and overall survival. In B-lymphoma cells, the mutation or knockdown of CREBBP or EP300 inhibited H3K27 acetylation, downregulated FBXW7 expression, activated the NOTCH pathway, and downstream CCL2/CSF1 expression, resulting in tumor-associated macrophage polarization to M2 phenotype and tumor cell proliferation. In B-lymphoma murine models, xenografted tumors bearing CREBBP/EP300 mutation presented lower H3K27 acetylation, higher M2 macrophage recruitment, and more rapid tumor growth than those with CREBBP/EP300 wild-type control via FBXW7-NOTCH-CCL2/CSF1 axis. Our work thus contributed to the understanding of aberrant histone acetylation regulation on tumor microenvironment as an alternative mechanism of tumor progression in DLBCL.

The molecular feature of macrophages in tumor immune microenvironment of glioma patients

“…They were detrimental in cancers such as pheochromocytoma and paraganglioma, kidney chromophobe and uveal melanoma, and protective in diffuse large B-cell lymphoma, prostate adenocarcinoma and thyroid cancer ( Fig. 5 D), which is partly in accordance with previous studies [59] , while not compatible with others [60] , [61] . The protective role of MScore in some cancers indicated the heterogeneity of the tumor microenvironment among different cancer types.…”

Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma

“…48 In contrast, another recent study found that DLBCL patients with CREBBP/EP300 mutations had significantly poorer survival and decreased peripheral blood lymphocyte to monocyte ratios, and that in DLBCL xenograft murine models, mutations in CREBBP and EP300 activated the NOTCH signaling pathway and promoted macrophage polarization to M2 phenotype. 49 In summary, KMT2D nonsynonymous mutations are associated with DLBCL genomic instability, and genomic complexity is associated with poor prognosis and decreased T cells and PD-L1 expression in macrophages and B cells in DLBCL with wild-type TP53. Further studies elucidating the oncogenic and neoantigen roles of DLBCL mutations in DLBCL patients are needed, as well as the therapeutic implications of genetic and immune biomarkers.…”

“… 48 In contrast, another recent study found that DLBCL patients with CREBBP / EP300 mutations had significantly poorer survival and decreased peripheral blood lymphocyte to monocyte ratios, and that in DLBCL xenograft murine models, mutations in CREBBP and EP300 activated the NOTCH signaling pathway and promoted macrophage polarization to M2 phenotype. 49 …”

Targeting the tumor microenvironment in B-cell lymphoma: challenges and opportunities

“…CCR2 inhibitors induce the accumulation of monocytes in bone marrow, resulting in reduced numbers of TAMs [ 51 ]. Yao et al reported that CREBBP/EP300 mutations could regulate the FBXW7-NOTCH-CCL2/CSF1, polarizing TAMs to the M2 phenotype and promoting cell proliferation in DLBCL [ 52 ].…”