Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussel, Belgium.
Cancers (Basel). 2013 Apr 15;5(2):430-61. doi: 10.3390/cancers5020430.
Multiple myeloma (MM) is an incurable B-cell malignancy. Therefore, new targets and drugs are urgently needed to improve patient outcome. Epigenetic aberrations play a crucial role in development and progression in cancer, including MM. To target these aberrations, epigenetic modulating agents, such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), are under intense investigation in solid and hematological cancers. A clinical benefit of the use of these agents as single agents and in combination regimens has been suggested based on numerous studies in pre-clinical tumor models, including MM models. The mechanisms of action are not yet fully understood but appear to involve a combination of true epigenetic changes and cytotoxic actions. In addition, the interactions with the BM niche are also affected by epigenetic modulating agents that will further determine the in vivo efficacy and thus patient outcome. A better understanding of the molecular events underlying the anti-tumor activity of the epigenetic drugs will lead to more rational drug combinations. This review focuses on the involvement of epigenetic changes in MM pathogenesis and how the use of DNMTi and HDACi affect the myeloma tumor itself and its interactions with the microenvironment.
多发性骨髓瘤（MM）是一种不可治愈的 B 细胞恶性肿瘤。因此，迫切需要新的靶点和药物来改善患者的预后。表观遗传异常在癌症的发展和进展中起着至关重要的作用，包括 MM。为了靶向这些异常，表观遗传调节剂，如 DNA 甲基转移酶抑制剂（DNMTi）和组蛋白去乙酰化酶抑制剂（HDACi），正在实体瘤和血液系统恶性肿瘤的研究中受到广泛关注。基于大量临床前肿瘤模型，包括 MM 模型，研究表明，这些药物单独使用或联合使用具有临床获益。作用机制尚不完全清楚，但似乎涉及真正的表观遗传改变和细胞毒性作用的组合。此外，与 BM 龛的相互作用也受到表观遗传调节剂的影响，这将进一步决定体内疗效，从而影响患者的预后。更好地了解表观遗传药物抗肿瘤活性的分子事件将导致更合理的药物联合治疗。本文综述了表观遗传改变在 MM 发病机制中的作用，以及 DNMTi 和 HDACi 的应用如何影响骨髓瘤肿瘤本身及其与微环境的相互作用。
