Epigenomic reprogramming via HRP2-MINA dictates response to proteasome inhibitors in multiple myeloma with t(4;14) translocation
Jingjing Wang, … , Lirong Zhang, Zhiqiang Liu
Jingjing Wang, … , Lirong Zhang, Zhiqiang Liu
Published February 15, 2022
Citation Information: J Clin Invest. 2022;132(4):e149526. https://doi.org/10.1172/JCI149526.
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Research Article Cell biology Hematology

Epigenomic reprogramming via HRP2-MINA dictates response to proteasome inhibitors in multiple myeloma with t(4;14) translocation

Abstract

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.

Authors

Jingjing Wang, Xu Zhu, Lin Dang, Hongmei Jiang, Ying Xie, Xin Li, Jing Guo, Yixuan Wang, Ziyi Peng, Mengqi Wang, Jingya Wang, Sheng Wang, Qian Li, Yafei Wang, Qiang Wang, Lingqun Ye, Lirong Zhang, Zhiqiang Liu

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Figure 1

In vivo CRISPR library screening identified HRP2 as a key negative regulator of bortezomib resistance.

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In vivo CRISPR library screening identified HRP2 as a key negative regul...
(A) Diagram of the genome-wide CRISPR/Cas9 screening system in a NSG femur bone marrow–bearing MM model. The 3 most obviously changed tumors from 9 mice per group were chosen for screening. gDNA, genomic DNA. (B) Volcano plot illustrating the depleted genes in the negative selection and the enriched genes in the positive selection. (C) Illustration of the top 10 gene candidates from the above screening. (D) HRP2 expression in 12 categories of tumor samples from the CCLE database. *P < 0.05 and **P < 0.02, by 2-sided Student’s t test. (E) Expression of HRP2 in bone marrow plasma cells from healthy donors (nontarget control [NT ctrl], n = 22), patients with MGUS (n = 44), and patients with SMM (n = 12) from the GSE5900 cohort. ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CML, chronic myelogenous leukemia. (F) HRP2 expression in patients with MM showed all kinds of responses (All-R, n = 12) or a nonresponse (Non-R, n = 12). (G) Expression trend of the HRP2 gene before and after a bortezomib-based treatment regimen: 7 patients with MM showed a CR and 5 patients with MM showed disease progression. (H) Quantification of HRP2+ cells in an immunohistochemical assay for 6 patients with a CR and 6 patients with RR bone marrow biopsies. T, treatment. (I) Correlation of HRP2 mRNA expression with overall survival (OS) in myeloma patients from Mulligan’s database (n = 188, GSID: GS-DT-52). The cutoff was the median of HRP2 expression. P values were determined by Pearson’s coefficient and log-rank test (I) and Student’s t test (E, F, and H).