Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
Blood. 2018 Aug 9;132(6):577-586. doi: 10.1182/blood-2018-01-828418. Epub 2018 Jun 28.
Primary effusion lymphoma (PEL) is an aggressive cancer with few treatment options. The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide have recently been shown to kill PEL cell lines, and lenalidomide is in clinical trials against PEL. IMiDs bind to the CRL4 E3 ubiquitin ligase complex, leading to the acquisition of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), casein kinase 1 α (CK1α), and zinc finger protein 91 (ZFP91) as neosubstrates. IMiDs are effective against multiple myeloma because of degradation of IKZF1 and IKZF3 and the consequent loss of interferon regulatory factor 4 (IRF4) and MYC expression. Lenalidomide is also effective in chromosome 5q deletion-associated myelodysplastic syndrome as a result of degradation of CK1α. An essential IKZF1-IRF4-MYC axis has recently been proposed to underlie the toxicity of IMiDs in PEL. Here, we further investigate IMiD effectors in PEL cell lines, based on genome-wide CRISPR/Cas9 screens for essential human genes. These screens and extensive validation experiments show that, of the 4 neosubstrates, only CK1α is essential for the survival of PEL cell lines. In contrast, IKZF1 and IKZF3 are dispensable, individually or in combination. IRF4 was critical in all 8 PEL cell lines tested, and surprisingly, IMiDs triggered downregulation of IRF4 expression independently of both IKZF1 and IKZF3. Reexpression of CK1α and/or IRF4 partially rescued PEL cell lines from IMiD-mediated toxicity. In conclusion, IMiD toxicity in PEL cell lines is independent of IKZF1 and IKZF3 but proceeds through degradation of the neosubstrate CK1α and downregulation of IRF4.
原发性渗出性淋巴瘤（PEL）是一种侵袭性癌症，治疗选择有限。免疫调节药物（IMiD）来那度胺和泊马度胺最近已被证明可杀死 PEL 细胞系，并且来那度胺正在临床试验中针对 PEL。IMiD 与 CRL4 E3 泛素连接酶复合物结合，导致获得 Ikaros 家族锌指蛋白 1 和 3（IKZF1 和 IKZF3）、酪蛋白激酶 1α（CK1α）和锌指蛋白 91（ZFP91）作为新底物。由于 IKZF1 和 IKZF3 的降解以及随之而来的干扰素调节因子 4（IRF4）和 MYC 表达的丧失，IMiD 对多发性骨髓瘤有效。来那度胺还可有效治疗染色体 5q 缺失相关骨髓增生异常综合征，这是由于 CK1α 的降解。最近提出了一个基本的 IKZF1-IRF4-MYC 轴，作为 IMiD 在 PEL 中的毒性基础。在这里，我们根据全基因组 CRISPR/Cas9 筛选必需的人类基因，进一步研究了 PEL 细胞系中的 IMiD 效应物。这些筛选和广泛的验证实验表明，在 4 个新底物中，只有 CK1α 对 PEL 细胞系的存活至关重要。相比之下，IKZF1 和 IKZF3 是可有可无的，单独或组合使用。IRF4 在所有 8 种测试的 PEL 细胞系中均至关重要，令人惊讶的是，IMiD 独立于 IKZF1 和 IKZF3 触发 IRF4 表达的下调。CK1α 和/或 IRF4 的重新表达部分挽救了 PEL 细胞系免受 IMiD 介导的毒性。总之，IMiD 在 PEL 细胞系中的毒性独立于 IKZF1 和 IKZF3，但通过降解新底物 CK1α 和下调 IRF4 进行。
