An epigenetic pathway regulates MHC-II expression and function in B cell lymphoma models
Te Zhang, … , Zibo Zhao, Lu Wang
Te Zhang, … , Zibo Zhao, Lu Wang
Published January 16, 2025
Citation Information: J Clin Invest. 2025;135(2):e179703. https://doi.org/10.1172/JCI179703.
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Research Article Oncology

An epigenetic pathway regulates MHC-II expression and function in B cell lymphoma models

Abstract

Mutations or homozygous deletions of MHC class II (MHC-II) genes are commonly found in B cell lymphomas that develop in immune-privileged sites and have been associated with patient survival. However, the mechanisms regulating MHC-II expression, particularly through genetic and epigenetic factors, are not yet fully understood. In this study, we identified a key signaling pathway involving the histone H2AK119 deubiquitinase BRCA1 associated protein 1 (BAP1), the interferon regulatory factor interferon regulatory factor 1 (IRF1), and the MHC-II transactivator class II transactivator (CIITA), which directly activates MHC-II gene expression. Disruption of the BAP1/IRF1/CIITA axis leads to a functional attenuation of MHC-II expression and MHC-II–dependent immune cell infiltration, leading to accelerated tumor growth in immunocompetent mice. Additionally, we demonstrated that pharmacological inhibition of polycomb repressive complex 1 (PRC1) — which deposits histone H2K119Ub and opposes BAP1 activity — can restore MHC-II gene expression in BAP1-deficient B cell lymphoma cells. These findings suggest that BAP1 may function as a tumor suppressor by regulating the tumor microenvironment and immune response. Our study also establishes the rationale for therapeutic strategies to restore tumor-specific MHC-II expression and enhance immunotherapy outcomes at epigenetic levels in B cell lymphoma treatment.

Authors

Te Zhang, Oguzhan Beytullahoglu, Rima Tulaiha, Amanda Luvisotto, Aileen Szczepanski, Natsumi Tsuboyama, Zibo Zhao, Lu Wang

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Figure 4

Pharmacological inhibition of PRC1 activity restores the transcription defect induced by BAP1 loss.

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Pharmacological inhibition of PRC1 activity restores the transcription d...
(A) The A20 BAP1-KO cells were treated with various concentrations of PRC1 inhibitor RB-3 for 6 days. The protein levels of H2AK119Ub and RING1B were determined by Western blot. Representative blot from 2 biological repeats. (B) The log2 fold change heatmap shows the H2AK119Ub levels in A20 BAP1-KO cells treated with either DMSO or RB-3. (C) The A20 BAP1-WT or -KO cells were treated with either DMSO or RB-3 for 6 days. The gene-expression profiles for each condition were determined by RNA-Seq. (D) The Venn diagram shows the overlap between BAP1 targeted genes and RB-3 rescued genes. (E) The pathway analysis with the 860 BAP1 targeted genes that were restored by RB-3 treatment. (F) The A20 BAP1-WT cells were treated with DMSO for 6 days, and the BAP1-KO cells were treated with either DMSO or RB-3 (5 μM) for 6 days. The mRNA levels of MHC-II cluster genes in each treatment were determined by RNA-Seq. (G) The BAP1-KO A20 cells were treated with either DMSO or RB-3 (10 μM) for 6 days. The protein levels of MHC-II were determined by FACS analysis. (H) The A20 BAP1-WT cells were treated with DMSO for 6 days, and the BAP1-KO cells were treated with either DMSO or various concentrations of RB-3 for 6 days. The IRF1 protein levels were determined by Western blot. Representative blot from 2 biological repeats. (I and J) The mRNA levels of Irf1 (I) and Ciita mRNA (J) were determined by real-time PCR. n = 3 technical replicates. Data are represented as mean ± SD. (K and L) The BAP1-KO cells were treated with RB-3 (10 μM) or/and GSK126 (5 μM) for 6 days. The protein levels of H2AK119Ub and H3K27me3 were determined by Western blot. (K) Representative blot from 2 biological repeats. The protein levels of cell surface MHC-II molecules were determined by FACS analysis (L).