Cyclosporine Broadens the Therapeutic Potential of Lenalidomide in Myeloid Malignancies.
Cyclosporine Broadens the Therapeutic Potential of Lenalidomide in Myeloid Malignancies.
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DOI：
10.33696/immunology.2.049
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Fang J
中科院分区：
文献类型：
--
作者：
Dou A;Fang J
免疫调节药物来那度胺用于治疗某些恶性血液病，包括骨髓增生异常综合征（MDS）。来那度胺与cereblon（CRBN）（CRL 4CRBN E3泛素连接酶复合物的组分）相互作用，导致底物（如转录因子Ikaros（Ikaros家族锌指1，IKZF 1））的泛素化和随后降解。通过基因组功能缺失筛选，我们最近发现了来那度胺在MDS中介导的两种新途径。本文就这两条通路的研究进展及其临床意义作一综述。G蛋白偶联受体68（GPR 68）或内源性钙调磷酸酶（CaN）抑制剂、钙调磷酸酶1（RCAN 1）调节剂的耗竭可逆转来那度胺对MDSL细胞（一种MDS细胞系）的抑制作用。有趣的是，用来那度胺处理后，MDSL细胞中GPR 68和RCAN 1的表达水平均上调，这取决于IKZF 1的减少，表明IKZF 1作为GPR 68和RCAN 1的转录阻遏物发挥作用。机制研究显示，GPR 68的上调或激活诱导了MDSL细胞中的Ca 2 +/钙蛋白酶促凋亡通路，而RCAN 1的上调抑制了CaN促存活通路。值得注意的是，药理学CaN抑制剂环孢菌素增强了MDS和急性髓性白血病（AML）对来那度胺的敏感性。令人惊讶的是，来那度胺预处理逆转了环孢素对T淋巴细胞的免疫抑制作用。我们的研究表明，来那度胺介导IKZF 1的降解，导致GPR 68和RCAN 1的去抑制，分别激活Ca 2 +/钙蛋白酶促凋亡途径和抑制CaN促存活途径。我们的研究表明，环孢霉素扩展了来那度胺对骨髓恶性肿瘤的治疗潜力，而不损害免疫功能。
The immunomodulatory drug lenalidomide is used for the treatment of certain hematologic malignancies, including myelodysplastic syndromes (MDS). Lenalidomide interacts with cereblon (CRBN), a component of the CRL4CRBN E3 ubiquitin ligase complex, leading to ubiquitination and subsequent degradation of substrates, such as transcription factor Ikaros (Ikaros family zinc finger 1, IKZF1). With a genome loss of function screen, we recently identified two novel pathways mediated by lenalidomide in MDS. In this review, we summarized the major findings of these two pathways and their clinical implications. Depletion of G protein-coupled receptor 68 (GPR68) or an endogenous calcineurin (CaN) inhibitor, regulator of calcineurin 1 (RCAN1), reversed the inhibitory effect of lenalidomide on MDSL cells, an MDS cell line. Intriguingly, both GPR68 and RCAN1 expression levels were upregulated in MDSL cells after treatment with lenalidomide that was dependent on diminishment of IKZF1, indicating that IKZF1 functioned as a transcription repressor for GPR68 and RCAN1. Mechanistic studies revealed that upregulation or activation of GPR68 induced a Ca2+/calpain pro-apoptotic pathway, while upregulation of RCAN1 inhibited the CaN pro-survival pathway in MDSL cells. Notably, the pharmacological CaN inhibitor, cyclosporine, enhanced the sensitivity to lenalidomide in MDS as well as acute myeloid leukemia (AML). Surprisingly, pretreatment with lenalidomide reversed the immunosuppressive effects of cyclosporine on T lymphocytes. Our studies suggest that lenalidomide mediates degradation of IKZF1, leading to derepression of GPR68 and RCAN1 that activates the Ca2+/calpain pro- apoptotic pathway and inhibits the CaN pro-survival pathway, respectively. Our studies implicate that cyclosporine extends the therapeutic potential of lenalidomide to myeloid malignancies without compromising immune function.