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Published on: January 7, 2019
BMP-ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B-Cell Lymphoma
Dongdong Liu1, Zhen Li1, Dongxia Tan1
1Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China.
Abstract:
EZH2 is the catalytic subunit of the histone methyltransferase Polycomb Repressive Complex 2 (PRC2), and its somatic activating mutations drive lymphoma, particularly the germinal center B-cell type. Although PRC2 inhibitors, such as tazemetostat, have demonstrated anti-lymphoma activity in patients, the clinical efficacy is not limited to EZH2-mutant lymphoma. In this study, Activin A Receptor Type 1 (ACVR1), a type I Bone Morphogenetic Protein (BMP) receptor, is identified as critical for the anti-lymphoma efficacy of PRC2 inhibitors through a whole-genome CRISPR screen. BMP6, BMP7, and ACVR1 are repressed by PRC2-mediated H3K27me3, and PRC2 inhibition upregulates their expression and signaling in cell and patient-derived xenograft models. Through BMP-ACVR1 signaling, PRC2 inhibitors robustly induced cell cycle arrest and B cell lineage differentiation in vivo. Remarkably, blocking ACVR1 signaling using an inhibitor or genetic depletion significantly compromised the in vitro and in vivo efficacy of PRC2 inhibitors. Furthermore, high levels of BMP6 and BMP7, along with ACVR1, are associated with longer survival in lymphoma patients, underscoring the clinical relevance of this study. Altogether, BMP-ACVR1 exhibits anti-lymphoma function and represents a critical PRC2-repressed pathway contributing to the efficacy of PRC2 inhibitors.
Insights
Polycomb Repressive Complex 2 (PRC2) inhibitors show anti-lymphoma effects by upregulating Bone Morphogenetic Protein (BMP) signaling via ACVR1. This pathway is crucial for PRC2 inhibitor efficacy and is linked to better patient survival in lymphoma.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), drives lymphoma development, particularly germinal center B-cell lymphoma.
- PRC2 inhibitors like tazemetostat exhibit anti-lymphoma activity, but their efficacy extends beyond EZH2-mutant cases.
Purpose of the Study:
- To identify novel pathways mediating the anti-lymphoma efficacy of PRC2 inhibitors.
- To elucidate the role of Bone Morphogenetic Protein (BMP) signaling in PRC2 inhibitor response.
Main Methods:
- Whole-genome CRISPR screening to identify genetic dependencies.
- Quantitative real-time PCR and Western blotting to assess gene and protein expression.
- In vitro and in vivo assays using cell lines and patient-derived xenografts.
- Pharmacological inhibition and genetic depletion of key signaling molecules.
Main Results:
- Activin A Receptor Type 1 (ACVR1) was identified as critical for PRC2 inhibitor efficacy.
- PRC2 inhibition upregulates BMP6, BMP7, and ACVR1 expression, activating BMP-ACVR1 signaling.
- BMP-ACVR1 signaling induces cell cycle arrest and B cell differentiation in lymphoma models.
- Inhibition of ACVR1 signaling abrogates the anti-lymphoma effects of PRC2 inhibitors.
- High expression of BMP6, BMP7, and ACVR1 correlates with improved survival in lymphoma patients.
Conclusions:
- The BMP-ACVR1 pathway is a critical PRC2-repressed axis that mediates the anti-lymphoma activity of PRC2 inhibitors.
- Targeting the BMP-ACVR1 pathway may enhance therapeutic strategies for lymphoma.
- BMP-ACVR1 signaling represents a potential biomarker for predicting response to PRC2 inhibitors.
