The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
Blood. 2018 Nov 15;132(20):2166-2178. doi: 10.1182/blood-2018-05-850727. Epub 2018 Sep 18.
Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted /Ikaros and /Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC "axis," as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including , and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies.
最近的研究表明，免疫调节药物（IMiDs）导致转录因子 Ikaros 和 Aiolos 的降解。然而，它们的缺失随后如何导致多发性骨髓瘤（MM）细胞死亡尚不清楚。使用 CRISPR-Cas9 基因组编辑，我们已经在人 MM 细胞系中删除了 /Ikaros 和 /Aiolos，以进一步深入了解它们的下游基因调控网络。单独失活任一个因子都能重现 IMiDs 的细胞内在作用，导致细胞周期停滞和凋亡诱导。此外，对它们缺失导致的转录变化的评估表明与来那度胺治疗有显著重叠。这并不依赖于 IRF4-MYC“轴”的减少，因为尽管发生了细胞死亡，但两种蛋白质都没有持续下调，并且过表达这两种因子都不能挽救 Ikaros 的缺失。重要的是，Ikaros 和 Aiolos 抑制干扰素刺激基因（ISGs）的表达，包括 ，它们的缺失导致干扰素样反应的激活，导致 MM 细胞死亡。Ikaros/Aiolos 通过与 MM 中的核小体重塑和去乙酰化酶复合物相互作用抑制 表达。IMiD 诱导的 Ikaros 缺失或干扰素治疗导致 MM 细胞表面 CD38 表达上调，为达雷妥尤单抗诱导的 NK 细胞介导的抗体依赖性细胞毒性作用做好准备。这些结果进一步深入了解了 IMiDs 的作用机制，并为与抗 CD38 单克隆抗体联合提供了机制上的依据。
