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 5

Loss of BAP1 reduces immune cell infiltration and promotes B cell lymphoma growth in vivo.

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Loss of BAP1 reduces immune cell infiltration and promotes B cell lympho...
(A) The cell growth rate of A20 BAP1-WT and -KO cells was determined by cell counting assay. (B) 2 × 106 of BAP1-WT and BAP1-KO clones were inoculated into the right flank of 6-week-old nude mice. The tumor size was measured every day for 1 week after inoculation. (C) Images of representative tumor tissue samples from each mouse were taken at the end of the experiment. (D) 5 × 106 of BAP1-WT and BAP1-KO clones were inoculated into the right flank of 6-week-old BALB/c mice. The tumor size was measured every day for 2 weeks after the inoculation. Data are represented as mean ± SEM. A 2-tailed unpaired Student’s t test was used for statistical analysis. **P < 0.01; *P < 0.05. (E) When each tumor reached 1 cm3, the mouse was euthanized, and the survival probability was shown. (F) Tumor tissue from both BAP1-WT and BAP1-KO was harvested and subjected to scRNA-Seq. The UMAP analysis identifies different clusters of cell populations within the tumor tissue based on the gene-expression profiles. (G) The bar plot shows the percentage of each cell cluster in the tumor tissues. (H) The violin plot shows the expression levels of Irf1, Ciita, and MHC-II cluster genes in BAP1-WT and -KO tumor cell population. (I) Immune cells from the first clustering were isolated (T cells and macrophages) and reclustered with UMAP algorithm. (J) The percentages of each type of immune cells were calculated in BAP1-WT and -KO A20 tumors and are shown in the bar plot. (K) The IHC staining was performed with CD4-specific antibody in BAP1-WT and -KO tumor tissues. Scale bars: 10 μm.