Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q.
Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q.
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DOI：
10.3390/cancers13205084
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发表时间：
2021-10-11
期刊：
影响因子：
5.2
通讯作者：
Fang J
中科院分区：
文献类型：
--
作者：
Park I;Phan TM;Fang J
来那度胺是一种免疫调节药物(IMiD)，已在多发性骨髓瘤(MM)和骨髓增生异常综合征(MDS)中取得临床疗效，染色体5q缺失(del(5q))。然而，许多接受来那度胺治疗的患者会复发并产生耐药性。最近的研究表明，来那度胺与一种名为Cereblon(CRBN)的蛋白质结合，导致IKZF1和IKZF3以及酪蛋白激酶1α的蛋白质水平降低。我们已经在髓系恶性肿瘤中发现了IKZF1下游的信号分子、G蛋白偶联受体68(GPR68)和钙调神经磷酸酶1(RCAN1)，包括MDS和有或没有del(5q)的急性髓系白血病(AML)。本文综述了来那度胺如何发挥抗肿瘤活性，并重点介绍了可增强来那度胺抗肿瘤活性的新的治疗靶点，重点是髓系恶性肿瘤，特别是没有del(5q)的肿瘤。来那度胺和其他免疫调节药物(IMids)已经在某些血液系统恶性肿瘤的亚型中取得了临床疗效，如多发性骨髓瘤、低风险骨髓增生异常综合征(MDS)和其他染色体5q缺失(del(5q))等。尽管来那度胺在血液系统恶性肿瘤中的临床反应良好，但复发和耐药仍然是基于IMiD的治疗中的一个问题。近十年来，发现了基于IMiD的抗肿瘤治疗的新的分子机制。IMID结合人小脑蛋白(CRBN)，CRL4 E3泛素连接酶复合体的底物受体。CRBN与IMIDS结合导致Ikaros家族锌指蛋白1和3(IKZF1和IKZF3)和酪蛋白激酶1α的降解。我们发现，来那度胺介导的IKZF1降解导致MDS和急性髓系白血病(AML)中G蛋白偶联受体68(GPR68)/钙/钙蛋白酶促凋亡通路的激活和钙调神经磷酸酶1(RCAN1)/钙调神经磷酸酶促生存通路的抑制。钙调神经磷酸酶抑制剂环孢素-A增强来那度胺在有或无del(5q)的MDS/AML中的抗白血病活性。这些发现拓宽了IMIDS的治疗潜力。现就来那度胺治疗髓系恶性肿瘤，特别是不含del(5q)的肿瘤的分子机制作一综述，以期突出新的治疗靶点。
Lenalidomide is an immunomodulatory drug (IMiD) that has achieved clinical efficacies in multiple myeloma (MM) and myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)). However, many patients treated with lenalidomide relapse and become resistant. Recent studies have demonstrated that lenalidomide binds a protein called cereblon (CRBN), leading to reduced protein levels of IKZF1 and IKZF3 and casein kinase 1 alpha. We have identified signaling molecules downstream of IKZF1, G protein-coupled receptor 68 (GPR68) and regulator of calcineurin 1 (RCAN1) in myeloid malignancies, including MDS and acute myeloid leukemia (AML) with or without del(5q). This review summarizes how lenalidomide exerts anti-tumor activity and highlights novel therapeutic targets that could enhance the anti-tumor activity of lenalidomide with a focus on myeloid malignancies, especially without del(5q). Lenalidomide as well as other immunomodulatory drugs (IMiDs) have achieved clinical efficacies in certain sub-types of hematologic malignancies, such as multiple myeloma, lower-risk myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)) and others. Despite superior clinical response to lenalidomide in hematologic malignancies, relapse and resistance remains a problem in IMiD-based therapy. The last ten years have witnessed the discovery of novel molecular mechanism of IMiD-based anti-tumor therapy. IMiDs bind human cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase complex. Binding of CRBN with IMiDs leads to degradation of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3) and casein kinase 1 alpha. We have found that lenalidomide-mediated degradation of IKZF1 leads to activation of the G protein-coupled receptor 68 (GPR68)/calcium/calpain pro-apoptotic pathway and inhibition of the regulator of calcineurin 1 (RCAN1)/calcineurin pro-survival pathway in MDS and acute myeloid leukemia (AML). Calcineurin inhibitor Cyclosporin-A potentiates the anti-leukemia activity of lenalidomide in MDS/AML with or without del(5q). These findings broaden the therapeutic potential of IMiDs. This review summarizes novel molecular mechanism of lenalidomide in myeloid malignancies, especially without del(5q), in the hope to highlight novel therapeutic targets.
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