Resistance to the hypomethylating agents (HMAs) 5-azacytidine (AZA) and 5-aza-2′-deoxycytidine (DAC) represents a major obstacle in the treatment of elderly patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) which are not suitable for hematopoietic stem cells transplantation. Approximately 50 % of patients do not respond to HMA treatment because of intrinsic (primary) resistance, while others could acquire drug resistance during the repeated cycles of the treatment. To prevent, delay or surmount resistance development, the molecular mechanisms underlying drug resistance must be first identified. This is crucial as no further standard therapeutic opportunities are available for these patients who failed hypomethylating agents-based treatment. The current review provides an updated information about the different mechanisms that may contribute to the development of resistance to HMAs. Despite the similar structure and mechanism of action of HMA, several studies did not report the expected development of cross-resistance. It is clear that in addition to the common modalities of chemoresistance, there must be some specific mechanisms of drug resistance. Changes in transport and metabolism of HMAs are among the most studied mechanisms of resistance. Drug uptake provided by two solute carrier (SLC) families: SLC28 and SLC29 (also known as the concentrative and equilibrative nucleoside transporter families, respectively), could represent one of the mechanisms of cross-resistance. Changes in the metabolism of these drugs are the most likely mechanism responsible for the unique mode of resistance to AZA and DAC. Deoxycytidine kinase and uridine-cytidine kinase due to their necessity for drug activation, each could represent one of the response markers to treatment with DAC and AZA, respectively. Other mechanisms involved in the development of resistance common for both drugs involved: i. increased DNA repair (caused for example by constitutive activation of the ATM/BRCA1 pathway and inhibition of p53-dependent apoptosis); ii. changes in the regulation of apoptosis/disrupted apoptotic pathways (specifically increased levels of the anti-apoptotic protein BCL2) and iii. increased resilience of leukemic stem cells to multiple drugs including HMAs. Despite intense research on the resistance of MDS and AML patients to HMAs, the mechanisms that may reduce the response of these cells to HMAs are not known in detail. We herein highlight the most important directions that future research should take.

对低甲基化药物 (HMA) 的耐药性 5-氮杂胞苷 (AZA) 和 5-aza-2'-脱氧胞苷 (DAC) 是治疗老年骨髓增生异常综合征 (MDS) 和急性髓性白血病 (AML) 患者的主要障碍。不适合造血干细胞移植。由于内在（原发性）耐药性，大约 50% 的患者对 HMA 治疗没有反应，而其他患者可能在治疗的重复周期中获得耐药性。为了预防、延缓或克服耐药性的发展，必须首先确定耐药性的分子机制。这一点至关重要，因为这些基于低甲基化药物治疗失败的患者没有进一步的标准治疗机会。目前的审查提供了有关可能导致对 HMA 产生耐药性的不同机制的最新信息。尽管 HMA 的结构和作用机制相似，但一些研究并未报告预期的交叉耐药性发展。很明显，除了常见的化学耐药形式外，还必须有一些特定的耐药机制。HMA 转运和代谢的变化是研究最多的抗性机制之一。由两个溶质载体 (SLC) 家族提供的药物吸收：SLC28 和 SLC29（也分别称为浓缩和平衡核苷转运蛋白家族）可能代表交叉耐药机制之一。这些药物代谢的变化是导致对 AZA 和 DAC 的独特耐药模式的最可能机制。脱氧胞苷激酶和尿苷-胞苷激酶由于它们对药物激活的必要性，它们分别代表了对 DAC 和 AZA 治疗的反应标志物之一。涉及两种药物共同耐药性发展的其他机制： i．增加的 DNA 修复（例如由 ATM/BRCA1 通路的组成性激活和 p53 依赖性细胞凋亡的抑制引起）；ii. 细胞凋亡调节/破坏的细胞凋亡途径的变化（特别是抗细胞凋亡蛋白BCL2的水平增加）和iii。增加白血病干细胞对包括 HMA 在内的多种药物的抵抗力。尽管对 MDS 和 AML 患者对 HMA 的耐药性进行了深入研究，可能会降低这些细胞对 HMA 反应的机制尚不清楚。我们在此强调了未来研究应该采取的最重要的方向。