BMP‐ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B‐Cell Lymphoma
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...
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| Format: | Article |
| Language: | English |
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Wiley
2024-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202306499 |
| _version_ | 1797242662703595520 |
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| author | Dongdong Liu Zhen Li Dongxia Tan Yang An Liping Chu Tiancheng Chen Weijia Li Ailin Zhou Ruijie Xiang Liye Zhang Yuxiu Qu Wei Qi |
| author_facet | Dongdong Liu Zhen Li Dongxia Tan Yang An Liping Chu Tiancheng Chen Weijia Li Ailin Zhou Ruijie Xiang Liye Zhang Yuxiu Qu Wei Qi |
| author_sort | Dongdong Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T18:42:47Z |
| format | Article |
| id | doaj.art-bb058e130a3d49ab935a94c8293a8e2d |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-24T18:42:47Z |
| publishDate | 2024-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-bb058e130a3d49ab935a94c8293a8e2d2024-03-27T09:39:53ZengWileyAdvanced Science2198-38442024-03-011112n/an/a10.1002/advs.202306499BMP‐ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B‐Cell LymphomaDongdong Liu0Zhen Li1Dongxia Tan2Yang An3Liping Chu4Tiancheng Chen5Weijia Li6Ailin Zhou7Ruijie Xiang8Liye Zhang9Yuxiu Qu10Wei Qi11Gene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaGene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaGene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaGene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaGene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaGene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaGene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaGene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaGene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaGene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaGene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaGene Editing Center School of Life Science and Technology ShanghaiTech University 393 Middle Huaxia Road Shanghai 201210 ChinaAbstract 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.https://doi.org/10.1002/advs.202306499ACVR1B‐cell lymphomabiomarkerBMPcancer therapeuticsPRC2 inhibitors |
| spellingShingle | Dongdong Liu Zhen Li Dongxia Tan Yang An Liping Chu Tiancheng Chen Weijia Li Ailin Zhou Ruijie Xiang Liye Zhang Yuxiu Qu Wei Qi BMP‐ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B‐Cell Lymphoma Advanced Science ACVR1 B‐cell lymphoma biomarker BMP cancer therapeutics PRC2 inhibitors |
| title | BMP‐ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B‐Cell Lymphoma |
| title_full | BMP‐ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B‐Cell Lymphoma |
| title_fullStr | BMP‐ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B‐Cell Lymphoma |
| title_full_unstemmed | BMP‐ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B‐Cell Lymphoma |
| title_short | BMP‐ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B‐Cell Lymphoma |
| title_sort | bmp acvr1 axis is critical for efficacy of prc2 inhibitors in b cell lymphoma |
| topic | ACVR1 B‐cell lymphoma biomarker BMP cancer therapeutics PRC2 inhibitors |
| url | https://doi.org/10.1002/advs.202306499 |
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