Epigenomic reprogramming via HRP2-MINA dictates response to proteasome inhibitors in multiple myeloma with t(4;14) translocation.
Epigenomic reprogramming via HRP2-MINA dictates response to proteasome inhibitors in multiple myeloma with t(4;14) translocation.
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通过 HRP2-MINA 进行的表观基因组重编程决定了 t(4;14) 易位多发性骨髓瘤对蛋白酶体抑制剂的反应
DOI：
10.1172/jci149526
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发表时间：
2022-02-15
期刊：
影响因子：
--
通讯作者：
Liu Z
中科院分区：
文献类型：
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作者：
Wang J;Zhu X;Dang L;Jiang H;Xie Y;Li X;Guo J;Wang Y;Peng Z;Wang M;Wang J;Wang S;Li Q;Wang Y;Wang Q;Ye L;Zhang L;Liu Z
染色体 t(4;14) (p16;q32) 易位驱动组蛋白甲基转移酶核 SET 结构域 2 (NSD2) 的高表达，并在多发性骨髓瘤 (MM) 的进化和进展中发挥重要作用。然而，NSD2 驱动的表观基因组改变对蛋白酶体抑制剂 (PI) 化疗耐药的机制尚不完全清楚。在携带骨髓的 MM 模型中使用 CRISPR/Cas9 sgRNA 文库，我们发现肝癌源性生长因子 2 (HRP2) 是 PI 化疗耐药性的抑制剂，并且其下调与临床反应不佳和预后较差相关。我们观察到硼替佐米耐药的 MM 细胞中 HRP2 受到抑制，并且 HRP2 的敲低会诱导对 PI 的显着耐受。此外，HRP2 的敲低会增加 H3K27me3 的水平，从而加剧转录组的改变，从而促进细胞存活并限制 ER 应激。从机制上讲，HRP2 识别 H3K36me2 并招募组蛋白去甲基酶 MYC 诱导的核抗原 (MINA) 来去除 H3K27me3。 Tazemetostat 是一种高度选择性的表观遗传抑制剂，可降低 H3K27me3 水平，在体外和体内协同增敏硼替佐米的抗 MM 作用。总的来说，这些结果提供了对 t(4;14) 易位 MM 患者化疗耐药起源的更好理解，并为管理具有不同基因组背景的 MM 患者提供了基本原理。
The chromosomal t(4;14) (p16;q32) translocation drives high expression of histone methyltransferase nuclear SET domain–containing 2 (NSD2) and plays vital roles in multiple myeloma (MM) evolution and progression. However, the mechanisms of NSD2-driven epigenomic alterations in chemoresistance to proteasome inhibitors (PIs) are not fully understood. Using a CRISPR/Cas9 sgRNA library in a bone marrow–bearing MM model, we found that hepatoma-derived growth factor 2 (HRP2) was a suppressor of chemoresistance to PIs and that its downregulation correlated with a poor response and worse outcomes in the clinic. We observed suppression of HRP2 in bortezomib-resistant MM cells, and knockdown of HRP2 induced a marked tolerance to PIs. Moreover, knockdown of HRP2 augmented H3K27me3 levels, consequentially intensifying transcriptome alterations promoting cell survival and restriction of ER stress. Mechanistically, HRP2 recognized H3K36me2 and recruited the histone demethylase MYC-induced nuclear antigen (MINA) to remove H3K27me3. Tazemetostat, a highly selective epigenetic inhibitor that reduces H3K27me3 levels, synergistically sensitized the anti-MM effects of bortezomib both in vitro and in vivo. Collectively, these results provide a better understanding of the origin of chemoresistance in patients with MM with the t(4;14) translocation and a rationale for managing patients with MM who have different genomic backgrounds.