The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma
The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma
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DOI：
10.18632/oncotarget.4603
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发表时间：
2015-09-15
期刊：
影响因子：
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通讯作者：
Cippitelli, Marco
中科院分区：
文献类型：
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作者：
Fionda, Cinzia;Abruzzese, Maria Pia;Cippitelli, Marco
免疫调节药物（IMiDs）在多发性骨髓瘤（MM）中具有有效的抗肿瘤活性，并且能够增强自然杀伤（NK）细胞的细胞毒性功能，NK细胞是针对MM的免疫应答的重要效应子。在这里，我们表明这些药物可以增强NKG 2D和DNAM-1激活受体配体云母和PVR/CD 155在人MM细胞系和原发性恶性浆细胞中的表达。通过shRNA干扰消除cereblon（CRBN）强烈损害了这些配体的上调，更有趣的是，IMiDs/CRBN介导的转录因子Ikaros（IKZF 1）、Aiolos（IKZF 3）和IRF 4的下调对于这些调节机制至关重要。事实上，IKZF 1或IKZF 3表达的shRNA敲低对于云母和PVR/CD 155表达的上调是必要的，也是足够的，表明这些转录因子可以抑制这些基因;因此，IKZF 1和IKZF 3蛋白对云母和PVR/CD 155启动子的直接相互作用和负面作用得到了证实。最后，云母表达在IRF 4沉默的细胞中增强，表明该转录因子对MM细胞中云母基因表达的特异性抑制作用。总之，这些发现描述了参与云母和PVR/CD 155基因表达调控的新分子途径，并鉴定了转录因子IKZF-1/IKZF-3和IRF 4作为MM细胞中这些基因的阻遏物。
Immunomodulatory drugs (IMiDs) have potent anti-tumor activities in multiple myeloma (MM) and are able to enhance the cytotoxic function of natural killer (NK) cells, important effectors of the immune response against MM. Here, we show that these drugs can enhance the expression of the NKG2D and DNAM-1 activating receptor ligands MICA and PVR/CD155 in human MM cell lines and primary malignant plasma cells. Depletion of cereblon (CRBN) by shRNA interference strongly impaired upregulation of these ligands and, more interestingly, IMiDs/CRBN-mediated downregulation of the transcription factors Ikaros (IKZF1), Aiolos (IKZF3) and IRF4 was critical for these regulatory mechanisms. Indeed, shRNA knockdown of IKZF1 or IKZF3 expression was both necessary and sufficient for the upregulation of MICA and PVR/CD155 expression, suggesting that these transcription factors can repress these genes; accordingly, the direct interaction and the negative role of IKZF1 and IKZF3 proteins on MICA and PVR/CD155 promoters were demonstrated. Finally, MICA expression was enhanced in IRF4-silenced cells, indicating a specific suppressive role of this transcription factor on MICA gene expression in MM cells.Taken together, these findings describe novel molecular pathways involved in the regulation of MICA and PVR/CD155 gene expression and identify the transcription factors IKZF-1/IKZF-3 and IRF4 as repressors of these genes in MM cells.