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.
View: Text | PDF
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

×

Figure 7

Tazemetostat sensitizes HRP2lo MM cells to bortezomib treatment in vitro and in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Tazemetostat sensitizes HRP2lo MM cells to bortezomib treatment in vitro...
(A) Cell viability of HRP2-KD LP-1 cells treated with 5 nM bortezomib and various concentrations of tazemetostat (TAZ) for 24 hours (n = 3). Data indicate the mean ± SD. (B) CI plots of tazemetostat and bortezomib combinations in HRP2-KD LP-1 cells. A CI of less than 1 defines a synergistic effect of 2 reagents (n = 3). (C) Apoptosis of nontarget control and HRP2-KD cells treated with bortezomib (5 nM) in the presence or absence of 2 dosages of tazemetostat for 48 hours (n = 3). Two-sided P values were determined by Student’s t test. Data indicate the mean ± SD. (D) Apoptosis of CD138+ plasma cells from patients with t(4;14) RR MM (n = 6). n = 3. Two-sided P values were determined by Student’s t test. Data indicate the mean ± SD. (E) Tumor growth of bortezomib-resistant LP-1 cells (3 × 106 cells/mouse) in NSG mice treated with vehicle, bortezomib, tazemetostat, or bortezomib plus tazemetostat (bortezomib, 1 mg/kg, i.p.; tazemetostat, 0.5 mg/kg, po; n = 12 mice/group). Two-sided P value of the mean ± SD was determined by 2-way ANOVA. (F) Survival rates of mice when their tumors had reached 15 mm3 in size (n = 12 mice/group). Two-sided P value was analyzed by log-rank test. Data indicate the mean ± SD. (G) Levels of M protein secreted in PDX mouse tail vein blood after treatment with bortezomib or with bortezomib plus tazemetostat (bortezomib, 1 mg/kg, i.p.; tazemetostat, 0.5 mg/kg, po; n = 6 mice/patient, n = 3 mice/group). P values were determined by Pearson’s coefficient and log-rank tests. (H) Representative micro-CT reconstructions of femurs bearing bortezomib-resistant LP-1 cells (5 × 105 cells/mouse; n = 8 mice/group). (I) Quantification of bone structure of mouse femurs (n = 6 mice/group). Two-sided P values of the mean ± SD were determined by Student’s t test.