Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
Cell Death Dis. 2019 Apr 11;10(4):324. doi: 10.1038/s41419-019-1562-9.
The transcription factor Myeloid Ecotropic Insertion Site 2 (MEIS2) has been identified as a cellular substrate of the E3-ubiquitin ligase complex CRL4-cereblon (CRBN) in crystal structure and by biochemical screen. Emerging evidence suggests that IMiDs can block MEIS2 from binding to CRBN facilitating the subsequent activation of a CRBN-E3-ubiquitin ligase activity and proteasome-mediated degradation of critical substrates regulators of Multiple Myeloma (MM) cell survival and proliferation. Bromodomain and Extra-Terminal (BET) family of proteins are important epigenetic regulators involved in promoting gene expression of several oncogenes, and many studies have revealed important anticancer activities mediated by BET inhibitors (BETi) in hematologic malignancies including MM. Here, we investigated MEIS2 in MM, the role of this protein as a modulator of IMiDs activity and the ability of BETi to inhibit its expression. Our observations indicate that inhibition of MEIS2 in MM cells by RNA interference correlates with reduced growth, induction of apoptosis and enhanced efficacy of different anti-MM drugs. In addition, MEIS2 regulates the expression of Cyclin E/CCNE1 in MM and induction of apoptosis after treatment with the CDK inhibitor Seliciclib/Roscovitine. Interestingly, modulation of MEIS2 can regulate the expression of NKG2D and DNAM-1 NK cell-activating ligands and, importantly, the activity of IMiDs in MM cells. Finally, BETi have the ability to inhibit the expression of MEIS2 in MM, underscoring a novel anticancer activity mediated by these drugs. Our study provides evidence on the role of MEIS2 in MM cell survival and suggests therapeutic strategies targeting of MEIS2 to enhance IMiDs anti-myeloma activity.
转录因子髓系细胞特异插入位点 2（MEIS2）已被鉴定为 E3 泛素连接酶复合物 CRL4-cereblon（CRBN）在晶体结构和生化筛选中的细胞底物。新出现的证据表明，IMiDs 可以阻止 MEIS2 与 CRBN 结合，从而促进随后的 CRBN-E3-泛素连接酶活性的激活和蛋白酶体介导的关键底物的降解，这些关键底物是多发性骨髓瘤（MM）细胞存活和增殖的调节剂。溴结构域和额外末端（BET）蛋白家族是重要的表观遗传调节剂，参与促进几个癌基因的基因表达，许多研究表明 BET 抑制剂（BETi）在血液恶性肿瘤中具有重要的抗癌活性，包括 MM。在这里，我们研究了 MM 中的 MEIS2，该蛋白作为 IMiDs 活性调节剂的作用以及 BETi 抑制其表达的能力。我们的观察表明，通过 RNA 干扰抑制 MM 细胞中的 MEIS2 与降低生长、诱导细胞凋亡和增强不同抗 MM 药物的疗效相关。此外，MEIS2 调节 MM 细胞中细胞周期蛋白 E/CCNE1 的表达，并在 CDK 抑制剂 Seliciclib/Roscovitine 治疗后诱导细胞凋亡。有趣的是，MEIS2 的调节可以调节 NKG2D 和 DNAM-1 NK 细胞激活配体的表达，重要的是，IMiDs 在 MM 细胞中的活性。最后，BETi 能够抑制 MM 中 MEIS2 的表达，突出了这些药物介导的新的抗癌活性。我们的研究提供了 MEIS2 在 MM 细胞存活中的作用的证据，并提出了针对 MEIS2 的治疗策略，以增强 IMiDs 的抗骨髓瘤活性。
