Kordella Chryssoula, Lamprianidou Eleftheria, Kotsianidis Ioannis
Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
Front Oncol. 2021 Mar 9;11:650473. doi: 10.3389/fonc.2021.650473. eCollection 2021.
Abnormal DNA methylation patterns are thought to drive the pathobiology of high-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukemia (AML). Sixteen years after their initial approval, the hypomethylating agents (HMAs), 5-azacytidine (AZA) and 5-aza-2'-deoxycytidine, remain the mainstay of treatment for HR-MDS and AML. However, a connection of the hypomethylating or additional effects of HMAs with clinical responses remains yet to be shown, and the mode of action of HMAs remains obscure. Given the relatively short-lived responses and the inevitable development of resistance in HMAs, a thorough understanding of the antineoplastic mechanisms employed by HMAs holds critical importance. Recent data in cancer cell lines demonstrate that reactivation of endogenous retroelements (EREs) and induction of a cell-intrinsic antiviral response triggered by RNA neotranscripts may underlie the antitumor activity of HMAs. However, data on primary CD34 cells derived from patients with HR-MDS failed to confirm a link between HMA-mediated ERE modulation and clinical response. Though difficult to reconcile the apparent discrepancy, it is possible that HMAs mediate their effects in more advanced levels of differentiation where cells become responsive to interferon, whereas, inter-individual variations in the process of RNA editing and, in particular, in the ADAR1/OAS/RNase L pathway may also confound the associations of clinical response with the induction of viral mimicry. Further studies along with clinical correlations in well-annotated patient cohorts are warranted to decipher the role of ERE derepression in the antineoplastic mechanisms of HMAs.
异常的DNA甲基化模式被认为是高危骨髓增生异常综合征（HR-MDS）和急性髓系白血病（AML）病理生物学的驱动因素。在首次获批16年后，低甲基化药物（HMA），即5-氮杂胞苷（AZA）和5-氮杂-2'-脱氧胞苷，仍然是HR-MDS和AML治疗的主要手段。然而，HMA的低甲基化或其他作用与临床反应之间的联系尚未得到证实，HMA的作用模式仍不清楚。鉴于HMA的反应相对短暂且不可避免地会产生耐药性，深入了解HMA所采用的抗肿瘤机制至关重要。最近在癌细胞系中的数据表明，内源性逆转录元件（ERE）的重新激活以及由RNA新转录本触发的细胞内在抗病毒反应可能是HMA抗肿瘤活性的基础。然而，来自HR-MDS患者的原代CD34细胞的数据未能证实HMA介导的ERE调节与临床反应之间的联系。尽管难以调和这一明显的差异，但有可能HMA在细胞对干扰素产生反应的更高级分化水平中介导其作用，而RNA编辑过程中的个体差异，特别是ADAR1/OAS/RNase L途径中的个体差异，也可能混淆临床反应与病毒模拟诱导之间的关联。有必要在注释完善的患者队列中进行进一步研究并结合临床相关性，以阐明ERE去抑制在HMA抗肿瘤机制中的作用。
