IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos
IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos
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DOI：
10.1182/blood-2018-05-850727
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发表时间：
2018-11-15
期刊：
影响因子：
20.3
通讯作者：
Nutt, Stephen L.
中科院分区：
文献类型：
--
作者：
Fedele, Pasquale L.;Willis, Simon N.;Nutt, Stephen L.
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，为什么他们的损失随后导致多发性骨髓瘤（MM）细胞死亡仍不清楚。使用CRISPR-Cas9基因组编辑，我们已经删除了人类MM细胞系中的IKZF 1/Ikaros和IKZF 3/Aiolos，以进一步了解其下游基因调控网络。任一因子单独失活重演了IMiD的细胞内在作用，导致细胞周期停滞和诱导细胞凋亡。此外，对由其损失引起的转录变化的评估表明与来那度胺治疗有惊人的重叠。这不依赖于IRF 4-MYC“轴”的减少，因为尽管发生细胞死亡，但两种蛋白质都没有持续下调，并且两种因子的过表达都未能挽救Ikaros损失。重要的是，Ikaros和Aiolos抑制干扰素刺激基因（ISG）的表达，包括CD 38，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中的核小体重塑和脱乙酰酶复合物相互作用抑制CD 38表达。IMiD诱导的Ikaros丢失或干扰素治疗导致MM细胞上CD 38表面表达上调，引发达雷妥珠单抗诱导的NK细胞介导的抗体依赖性细胞毒性。这些结果进一步深入了解了IMiD的作用机制，并为与抗CD 38单克隆抗体联合用药提供了机制依据。
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 IKZF1/Ikaros and IKZF3/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 CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 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.