The prognosis of AML patients with adverse genetics, such as a complex, monosomal karyotype and TP53 lesions, is still dismal even with standard chemotherapy. DNA-hypomethylating agent monotherapy induces an encouraging response rate in these patients. When combined with decitabine (DAC), all-trans retinoic acid (ATRA) resulted in an improved response rate and longer overall survival in a randomized phase II trial (DECIDER; NCT00867672). The molecular mechanisms governing this in vivo synergism are unclear. We now demonstrate cooperative antileukemic effects of DAC and ATRA on AML cell lines U937 and MOLM-13. By RNA-sequencing, derepression of >1200 commonly regulated transcripts following the dual treatment was observed. Overall chromatin accessibility (interrogated by ATAC-seq) and, in particular, at motifs of retinoic acid response elements were affected by both single-agent DAC and ATRA, and enhanced by the dual treatment. Cooperativity regarding transcriptional induction and chromatin remodeling was demonstrated by interrogating the HIC1, CYP26A1, GBP4, and LYZ genes, in vivo gene derepression by expression studies on peripheral blood blasts from AML patients receiving DAC + ATRA. The two drugs also cooperated in derepression of transposable elements, more effectively in U937 (mutated TP53) than MOLM-13 (intact TP53), resulting in a “viral mimicry” response. In conclusion, we demonstrate that in vitro and in vivo, the antileukemic and gene-derepressive epigenetic activity of DAC is enhanced by ATRA.
对于具有不良遗传特征的急性髓系白血病（AML）患者，例如复杂核型、单体核型及TP53病变者，即使采用标准化疗，其预后仍然不佳。DNA低甲基化剂单药治疗在这些患者中显示出令人鼓舞的反应率。在一项随机二期试验（DECIDER；NCT00867672）中，地西他滨（DAC）联合全反式维甲酸（ATRA）治疗提高了反应率并延长了总生存期，但其体内协同作用的分子机制尚不明确。本研究证实了DAC与ATRA对AML细胞系U937和MOLM-13具有协同抗白血病效应。通过RNA测序发现，双药治疗后超过1200个共同调控的转录本被解除抑制。染色质整体可及性（通过ATAC-seq检测）尤其是维甲酸反应元件基序区域，在单药DAC或ATRA作用下均发生改变，并在联合治疗中得到增强。通过对HIC1、CYP26A1、GBP4和LYZ基因的研究，证实了双药在转录诱导和染色质重塑方面的协同作用；对接受DAC＋ATRA治疗的AML患者外周血原始细胞的表达研究，进一步验证了体内基因解除抑制现象。两种药物在转座因子解除抑制方面也表现协同效应，该作用在U937（TP53突变型）中比MOLM-13（TP53野生型）更为显著，从而引发“病毒模拟”反应。综上所述，本研究证实无论在体外还是体内，ATRA均能增强DAC的抗白血病活性及基因解除抑制的表观遗传效应。
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