Background
Diffuse large B-cell lymphoma (DLBCL) is characterized by its aggressive nature and resistance to standard chemotherapy, necessitating the development of new therapeutic approaches. Histone acetylation, a crucial epigenetic modification, is globally decreased in DLBCL. Chidamide, a histone deacetylase (HDACs) inhibitor, has shown promise in certain lymphomas but its effectiveness in DLBCL remains under investigation.
Methods
RNA-seq and gene enrichment analysis were performed to identify chidamide's impact on the biological processes in DLBCL. The key factor influencing chidamide sensitivity was determined through correlation analysis, utilizing gene expression levels from the Cancer Cell Line Encyclopedia and IC50 values of four HDAC inhibitors across multiple cancer cell lines sourced from the Genomics of Drug Sensitivity database. Histone acetylation levels, HAT and HDAC enzyme activity analysis, and co-immunoprecipitation were performed to investigate the underlying mechanism through which BCL6 influences chidamide sensitivity. A search among small molecule drugs in clinical investigation aimed to find drugs inhibiting BCL6 to enhance DLBCL sensitivity to chidamide. Synergy between HDAC and BCL6 inhibition was explored through synergistic effects, ubiquitination, and proteasomal degradation analysis. DLBCL mouse models were utilized to evaluate the therapeutic potential of combining chidamide and lenalidomide in vivo. Additionally, chidamide's effects on macrophage polarization were investigated through RNA-seq analysis of M1, M2, and chidamide-treated M2 macrophages.
Results
Chidamide exhibited potent suppression of DLBCL both in vitro and in vivo (Figure 1A), exerting a significant impact on diverse biological processes in DLBCL. BCL6 inhibited chidamide-induced histone acetylation by recruiting HDACs, leading to drug resistance in DLBCL cells. Lenalidomide could target BCL6 degradation through the ubiquitination pathway and restored the sensitivity of drug-resistant DLBCL to chidamide (Figure 1B). Additionally, chidamide had an impact on the tumor microenvironment. Chidamide inhibited the activity of M2-like tumor-associated macrophages and redirected the polarization of macrophages toward the M1 phenotype. Moreover, we conducted a single-arm multicenter clinical trial to evaluate the safety and efficacy of chidamide in combination with lenalidomide in DLBCL.
Conclusions
These findings highlighted HDACs as a viable therapeutic strategy for DLBCL, providing valuable insights into chidamide's global impact on the disease. Furthermore, BCL6 was a pivotal determinant of chidamide sensitivity and a reliable biomarker for treatment response. Integrating HDAC and BCL6 inhibition held potential for personalized and effective DLBCL treatments.
Disclosures
No relevant conflicts of interest to declare.
