将新疗法与全反式维甲酸(ATRA)结合使用可以提高急性髓细胞性白血病(AML)治疗的效率。基于白血病细胞的转录组学概况对ATRA诱导的分化过程进行建模,从而鉴定出可用于增加ATRA治疗效果的关键靶标。基因组尺度转录组分析揭示了对HL-60细胞的ATRA处理的早期分子反应。在这项研究中,我们对暴露于ATRA3-72小时的HL-60、NB4和K562细胞进行了转录组学分析。在用ATRA处理3、12、24和72小时后,我们在HL-60细胞中发现222、391、359和1032个差异表达基因(DEG),以及NB4单元中的641、1037、1011和1499DEG。我们还在用ATRA处理24h和72h的K562细胞中发现538和119DEGs,分别。根据实验转录组数据,我们进行了分层建模并确定了细胞周期蛋白依赖性激酶6(CDK6),肿瘤坏死因子α(TNF-α),和转录阻遏物CUX1是HL-60,NB4和K562细胞系中对ATRA处理的分子反应的关键调节因子,分别。将基于TMT的质谱分析数据映射到建模方案上,我们测定了用ATRA治疗72小时的细胞中CDK6在蛋白质组水平的表达及其在转录组和蛋白质组水平的下调。CDK6抑制剂(palbociclib)和ATRA(维甲酸)的联合治疗可能是治疗急性髓性白血病(AML)的替代方法。
Combining new therapeutics with all-trans-retinoic acid (ATRA) could improve the efficiency of acute myeloid leukemia (AML) treatment. Modeling the process of ATRA-induced differentiation based on the transcriptomic profile of leukemic cells resulted in the identification of key targets that can be used to increase the therapeutic effect of ATRA. The genome-scale transcriptome analysis revealed the early molecular response to the ATRA treatment of HL-60 cells. In this study, we performed the transcriptomic profiling of HL-60, NB4, and
K562 cells exposed to ATRA for 3-72 h. After treatment with ATRA for 3, 12, 24, and 72 h, we found 222, 391, 359, and 1032 differentially expressed genes (DEGs) in HL-60 cells, as well as 641, 1037, 1011, and 1499 DEGs in NB4 cells. We also found 538 and 119 DEGs in
K562 cells treated with ATRA for 24 h and 72 h, respectively. Based on experimental transcriptomic data, we performed hierarchical modeling and determined cyclin-dependent kinase 6 (CDK6), tumor necrosis factor alpha (TNF-alpha), and transcriptional repressor CUX1 as the key regulators of the molecular response to the ATRA treatment in HL-60, NB4, and
K562 cell lines, respectively. Mapping the data of TMT-based mass-spectrometric profiling on the modeling schemes, we determined CDK6 expression at the proteome level and its down-regulation at the transcriptome and proteome levels in cells treated with ATRA for 72 h. The combination of therapy with a CDK6 inhibitor (palbociclib) and ATRA (tretinoin) could be an alternative approach for the treatment of acute myeloid leukemia (AML).