MLL rearrangement is one of the key drivers and generally regarded as an independent poor prognostic marker in acute leukemias. The standard of care for MLL-rearranged (MLL-r) leukemias has remained largely unchanged for the past 50 years despite unsatisfying clinical outcomes, so there is an urgent need for novel therapeutic strategies. An increasing body of evidence demonstrates that a vast number of epigenetic regulators are directly or indirectly involved in MLL-r leukemia, and they are responsible for supporting the aberrant gene expression program mediated by MLL-fusions. Unlike genetic mutations, epigenetic modifications can be reversed by pharmacologic targeting of the responsible epigenetic regulators. This leads to significant interest in developing epigenetic therapies for MLL-r leukemia. Intriguingly, many of the epigenetic enzymes also involve in DNA damage response (DDR), which can be potential targets for synthetic lethality-induced therapies. In this review, we will summarize some of the recent advances in the development of epigenetic and DDR therapeutics by targeting epigenetic regulators or protein complexes that mediate MLL-r leukemia gene expression program and key players in DDR that safeguard essential genome integrity. The rationale and molecular mechanisms underpinning the therapeutic effects will also be discussed with a focus on how these treatments can disrupt MLL-fusion mediated transcriptional programs and impair DDR, which may help overcome treatment resistance.

MLL重排是关键因素之一，通常被认为是急性白血病的独立不良预后指标。尽管临床效果不理想，但过去50年来，MLL重排（MLL-r）白血病的护理标准在很大程度上保持不变，因此迫切需要新的治疗策略。越来越多的证据表明，大量表观遗传调控因子直接或间接参与了MLL-r白血病，它们负责支持MLL融合介导的异常基因表达程序。与遗传突变不同，表观遗传修饰可通过负责任的表观遗传调节剂的药理作用逆转。这引起了对开发用于MLL-r白血病的表观遗传学疗法的极大兴趣。有趣的是 许多表观遗传酶也参与DNA损伤反应（DDR），这可能是合成致死性疗法的潜在靶标。在这篇综述中，我们将通过靶向介导MLL-r白血病基因表达程序的表观遗传调节剂或蛋白质复合物以及DDR中维护基本基因组完整性的关键参与者，总结表观遗传学和DDR治疗药物开发的最新进展。还将讨论支撑治疗效果的基本原理和分子机制，重点是这些治疗如何破坏MLL融合介导的转录程序并损害DDR，从而有助于克服治疗耐药性。我们将通过靶向介导MLL-r白血病基因表达程序的表观遗传调节剂或蛋白质复合物以及DDR中维护基本基因组完整性的关键参与者，总结表观遗传学和DDR治疗药物开发的最新进展。还将讨论支撑治疗效果的基本原理和分子机制，重点是这些治疗如何破坏MLL融合介导的转录程序并损害DDR，从而有助于克服治疗耐药性。我们将通过靶向介导MLL-r白血病基因表达程序的表观遗传调节剂或蛋白质复合物以及DDR中维护基本基因组完整性的关键参与者，总结表观遗传学和DDR治疗药物开发的最新进展。还将讨论支撑治疗效果的基本原理和分子机制，重点是这些治疗如何破坏MLL融合介导的转录程序并损害DDR，从而有助于克服治疗耐药性。