Department of Hematology, Guizhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China; Guizhou Medical University, Guiyang 550004, China.
Department of Hematology, Guizhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Guiyang 550004, China.
Exp Cell Res. 2018 Feb 15;363(2):196-207. doi: 10.1016/j.yexcr.2018.01.005. Epub 2018 Jan 6.
Inhibition of histone deacetylase (HDAC) is a promising therapeutic strategy for various hematologic cancers. Panobinostat has been approved for treating patients with multiple myeloma (MM) by the FDA. Since the mechanism for the resistance of panobinostat to MM remains elusive, we aimed to clarify this mechanism and the synergism of panobinostat with lenalidomide. The mRNA and protein of transcription factor IRF4 were overexpressed in CD138 mononuclear cells from MM patients compared with in those from healthy donors. Given that direct IRF4 inhibitors are clinically unavailable, we intended to explore the mechanism by which IRF4 expression was regulated in MM. Heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors, and its expression is positively correlated with IRF4 mRNA and protein expression levels. Herein, panobinostat induced acetylation of histone H3K9 and activation of caspase-3 in MM cells, being inversely correlated with the reduction of HO-1/IRF4/MYC protein levels. Adding Z-DEVD-FMK, a caspase-3 inhibitor, abolished the HO-1/IRF4 reduction by panobinostat alone or in combination with lenalidomide, suggesting that caspase-3-mediated HO-1/IRF4/MYC degradation occurred. Given that lenalidomide stabilized cereblon and facilitated IRF4 degradation in MM cells, we combined it with LBH589, an HDAC inhibitor. LBH589 and lenalidomide exerted synergistic effects, and LBH589 reversed the efficacy of lenalidomide on the resistance of CD138 primary MM cells, in part due to simultaneous suppression of HO-1, IRF4 and MYC. The results provide an eligible therapeutic strategy for targeting MM depending on the IRF4 network and clinical testing of this drug combination in MM patients.
组蛋白去乙酰化酶（HDAC）的抑制作用是治疗各种血液系统恶性肿瘤的一种很有前途的治疗策略。泛昔洛韦已被 FDA 批准用于治疗多发性骨髓瘤（MM）患者。由于泛昔洛韦对 MM 耐药的机制尚不清楚，我们旨在阐明这种机制以及泛昔洛韦与来那度胺的协同作用。与健康供者相比，来自 MM 患者的 CD138 单核细胞中转录因子 IRF4 的 mRNA 和蛋白表达过度。鉴于直接的 IRF4 抑制剂在临床上不可用，我们打算探索在 MM 中调节 IRF4 表达的机制。血红素加氧酶-1（HO-1）促进各种恶性肿瘤的生长和耐药性，其表达与 IRF4 mRNA 和蛋白表达水平呈正相关。在此，泛昔洛韦诱导 MM 细胞中组蛋白 H3K9 的乙酰化和 caspase-3 的激活，与 HO-1/IRF4/MYC 蛋白水平的降低呈负相关。添加 caspase-3 抑制剂 Z-DEVD-FMK 可消除泛昔洛韦单独或与来那度胺联合使用时对 HO-1/IRF4 减少的作用，表明 caspase-3 介导的 HO-1/IRF4/MYC 降解发生。鉴于来那度胺稳定 cereblon 并促进 MM 细胞中 IRF4 的降解，我们将其与 LBH589（一种 HDAC 抑制剂）联合使用。LBH589 和来那度胺具有协同作用，LBH589 逆转了来那度胺对 CD138 原发性 MM 细胞耐药性的疗效，部分原因是同时抑制了 HO-1、IRF4 和 MYC。这些结果为基于 IRF4 网络的 MM 提供了一种合格的治疗策略，并为在 MM 患者中进行这种药物组合的临床测试提供了依据。
