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

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小鼠浆细胞腹水中培育的小鼠细胞系，我们成功地将其移植到NOG受体小鼠中。接下来，我们研究了我们的小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，UNC1999对EZH2及其同系物EZH1的双重抑制显著抑制了细胞的生长。有趣的是，我们发现UTX的丢失和激活的BRAF V600E突变同时产生了对蛋白酶体抑制剂的耐药性。接下来，我们比较了EZH2和EZH1的双重抑制和EZH2作为蛋白酶体抑制剂的合作伙伴的特异性抑制，分别使用unc1999和GSK126。我们的结果表明，从组合指数来看，UNC1999表现出比GSK126更强的协同效应。接下来，我用强力霉素诱导的慢病毒载体在我们的UTX-/-BRAF V600E小鼠细胞系中过表达野生型UTX。我发现与对照细胞相比，UTX过表达对细胞的生长有明显的抑制作用。然而，我发现在对照细胞和UTX过表达细胞中，对特异的EZH2抑制剂GSK126、EZH2和EZH1的双重抑制剂UN1999以及蛋白酶体抑制剂bortezomib的敏感性没有差异。

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.