Mantle cell lymphoma (MCL) is a rare, aggressive, and heterogeneous subtype of B-cell non-Hodgkin lymphoma. Emerging evidence suggests that epigenetic abnormalities play a critical role in its pathogenesis. Histone deacetylase inhibitors (HDACi) have demonstrated potential as therapeutic agents, either alone or in combination with other treatments, offering a promising avenue for MCL management. In our previous study, proteomic and pathological analyses revealed elevated expression levels of HDAC1 in MCL cell lines and tissues. Transcriptomic analysis of MCL cell lines treated with chidamide demonstrated that the drug could induce transcriptional activation of downstream BET family proteins. Building on these findings, we aim to further explore synergistic effects of BET Inhibitors combine with chidamide in mantle cell lymphoma. Over the past decade, pathological samples from more than 50 MCL patients were collected to evaluate the expression of HDAC1, HDAC2, and HDAC6 antigens. Comprehensive clinical and pathological data were gathered, including laboratory results, imaging findings, initial treatment regimens, treatment responses, remission status, and overall survival outcomes. The expression levels of HDAC1, HDAC2, and HDAC6 antigens in MCL tissues were assessed by experienced pathologists using professional evaluation criteria. The results revealed that while both HDAC1 and HDAC2 are expressed in mantle cell lymphoma tissue samples—with strong expression observed for HDAC1—HDAC6 was not expressed. Mantle cell lymphoma cell line (Maver-1) was treated with varying doses of chidamide (0–30 μM) for 24, 48, and 72 hours. The cytotoxicity of the HDAC inhibitor was assessed using the CCK-8 assay. Results showed that the half-maximal inhibitory concentration (IC50) of chidamide at 48 hours was determined to be 0.9 μM, providing an optimal time point and dosage for subsequent omics and mechanistic studies. Furthermore, it was observed that chidamide exhibited a time- and dose-dependent cytotoxic effect on Maver-1 cells. The cells with chidamide (0.9 μM) for 48 hours, Western blot analysis was performed to evaluate the expression levels of HDAC1, HDAC2, and HDAC6 proteins. The results indicated that all three proteins were expressed at the cellular level. Consistent with clinical findings, HDAC1 showed high expression in Maver-1 cells. Notably, treatment with chidamide significantly reduced the expression levels of HDAC1. The cytotoxic effects of varying doses (0–20 μM) of the BET inhibitor JQ1 on the mantle cell lymphoma cell line (Maver-1) were assessed, and its half-maximal inhibitory concentration (IC50) was determined. Following treatment with chidamide (0.9 μM) for 48 hours, combined treatment with JQ1 at 14.2 μM was applied to evaluate cell cycle arrest in Maver-1 cells. The results showed that combination therapy significantly enhanced G2/M phase arrest, indicating a synergistic effect on disrupting the cell cycle. The synergistic effects of BET inhibitors may be linked to the proliferation of tumor-associated macrophages and modulation of the immune microenvironment. In future we would focus on the underlying mechanisms involving immune microenvironment regulation. This study represents the first exploration of dual epigenetic therapy in MCL. Our goal is to elucidate the mechanisms by which chidamide exerts its therapeutic effects in MCL through regulation of the BET signaling pathway, ultimately providing a theoretical foundation for dual epigenetic therapy in B-cell lymphoma.

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2025
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