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The role of UTX in the pathogenesis of multiple myeloma and its therapeutic applications

UTX在多发性骨髓瘤发病机制中的作用及其治疗应用

基本信息

批准号：
19K21281
负责人：
リズクモハメド・カーメル・アブデルバシール・ヘラル・オラ
金额：
$ 1.91万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Research Activity Start-up
财政年份：
2018
资助国家：
日本
起止时间：
2018-08-24 至 2020-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-19K21281/
关键词：
multiple myeloma EZH2 UTX UNC1999 GSK126 Multiple myeloma Epigenetics

项目摘要

In this study, I investigated the biological role of UTX in multiple myeloma.Using a murine cell line that we had developed from plasmacytic ascites derived from a moribund Utx -/- Braf V600E mouse, we successfully performed serial transplantation into NOG recipient mice.Next, we investigated the susceptibility of our murine cell line to novel and conventional anti-myeloma agents. We found that dual inhibition of EZH2 and its homolog EZH1 using UNC1999 significantly inhibited the growth of the cells compared to the specific inhibitor of EZH2, GSK126. Interestingly, we found that concurrent loss of Utx and the activating Braf V600E mutation conferred resistance to proteasome inhibitors. Next, we compared the dual inhibition of EZH2 and EZH1 with the specific inhibition of EZH2 as partners of proteasome inhibitors using UNC1999 and GSK126, respectively. Our results showed that UNC1999 exhibited stronger synergistic effects than GSK126 as evidenced by the combination index. This suggests that UNC1999 enhances bortezomib-induced cytotoxicity by blocking residual PRC2 activity through inhibition of EZH1.Next, I used doxycycline-inducible lentiviral vectors to overexpress wild type-UTX in our Utx -/- Braf V600E murine cell line. I found that UTX overexpression caused significant inhibition of the growth of the cells compared with control cells. However, I found no difference in the susceptibility to the specific EZH2 inhibitor GSK126, the dual inhibitor of EZH2 and EZH1 UNC1999 or the proteasome inhibitor bortezomib between the control and UTX overexpressing cells.

在这项研究中，我研究了 UTX 在多发性骨髓瘤中的生物学作用。使用我们从垂死的 Utx -/- Braf V600E 小鼠的浆细胞腹水中开发的鼠细胞系，我们成功地对 NOG 受体小鼠进行了连续移植。接下来，我们研究了我们的鼠细胞系对新型和传统抗骨髓瘤药物的敏感性。我们发现，与 EZH2 的特异性抑制剂 GSK126 相比，使用 UNC1999 对 EZH2 及其同源物 EZH1 的双重抑制可显着抑制细胞的生长。有趣的是，我们发现 Utx 的同时丢失和激活的 Braf V600E 突变赋予了对蛋白酶体抑制剂的抗性。接下来，我们分别使用 UNC1999 和 GSK126 比较了 EZH2 和 EZH1 的双重抑制与作为蛋白酶体抑制剂伙伴的 EZH2 的特异性抑制。我们的结果表明，如组合指数所示，UNC1999 表现出比 GSK126 更强的协同效应。这表明UNC1999通过抑制EZH1来阻断残留的PRC2活性，从而增强硼替佐米诱导的细胞毒性。接下来，我使用强力霉素诱导的慢病毒载体在我们的Utx -/- Braf V600E鼠细胞系中过表达野生型-UTX。我发现与对照细胞相比，UTX 过度表达导致细胞生长的显着抑制。然而，我发现对照细胞和 UTX 过表达细胞对特定 EZH2 抑制剂 GSK126、EZH2 和 EZH1 UNC1999 双重抑制剂或蛋白酶体抑制剂硼替佐米的敏感性没有差异。