BMP-ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B-Cell Lymphoma,Advanced Science

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BMP-ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B-Cell Lymphoma
Advanced Science ( IF 14.3 ) Pub Date : 2024-01-16 , DOI: 10.1002/advs.202306499
Dongdong Liu ₁ , Zhen Li ₁ , Dongxia Tan ₁ , Yang An ₁ , Liping Chu ₁ , Tiancheng Chen ₁ , Weijia Li ₁ , Ailin Zhou ₁ , Ruijie Xiang ₁ , Liye Zhang ₁ , Yuxiu Qu ₁ , Wei Qi _{1,

2}

Affiliation

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.

中文翻译：

BMP-ACVR1 轴对于 PRC2 抑制剂在 B 细胞淋巴瘤中的疗效至关重要

EZH2 是组蛋白甲基转移酶多梳抑制复合物 2 (PRC2) 的催化亚基，其体细胞激活突变可导致淋巴瘤，特别是生发中心 B 细胞类型的淋巴瘤。尽管 PRC2 抑制剂（例如他泽美司他）已在患者中表现出抗淋巴瘤活性，但临床疗效并不限于 EZH2 突变淋巴瘤。在这项研究中，通过全基因组 CRISPR 筛选，发现 1 型激活素 A 受体 (ACVR1)（一种 I 型骨形态发生蛋白 (BMP) 受体）对于 PRC2 抑制剂的抗淋巴瘤功效至关重要。 BMP6 、 BMP7和ACVR1受到 PRC2 介导的 H3K27me3 的抑制，PRC2 抑制会上调它们在细胞和患者来源的异种移植模型中的表达和信号传导。通过 BMP-ACVR1 信号传导，PRC2 抑制剂在体内强烈诱导细胞周期停滞和 B 细胞谱系分化。值得注意的是，使用抑制剂或基因敲除阻断 ACVR1 信号传导会显着损害 PRC2 抑制剂的体外和体内功效。此外，高水平的 BMP6 和 BMP7 以及 ACVR1 与淋巴瘤患者的较长生存期相关，这强调了这项研究的临床意义。总而言之，BMP-ACVR1 表现出抗淋巴瘤功能，并代表了有助于 PRC2 抑制剂疗效的关键 PRC2 抑制途径。

更新日期：2024-01-16

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