Resistance to chemotherapy is ultimately responsible for the majority of AML-related deaths, making the identification of resistance pathways a high priority. Transcriptomics approaches can be used to identify genes regulated at the level of transcription or mRNA stability but miss microRNA-mediated changes in translation, which are known to play a role in chemo-resistance. To address this, we compared miRNA profiles in paired chemo-sensitive and chemo-resistant subclones of HL60 cells and used a bioinformatics approach to predict affected pathways. From a total of 38 KEGG pathways implicated, TGF-β/activin family signaling was selected for further study. Chemo-resistant HL60 cells showed an increased TGF-β response but were not rendered chemo-sensitive by specific inhibitors. Differential pathway expression in primary AML samples was then investigated at the RNA level using publically available gene expression data in the TGCA database and by longitudinal analysis of pre- and post-resistance samples available from a limited number of patients. This confirmed differential expression and activity of the TGF-β family signaling pathway upon relapse and revealed that the expression of TGF-β and activin signaling genes at diagnosis was associated with overall survival. Our focus on a matched pair of cytarabine sensitive and resistant sublines to identify miRNAs that are associated specifically with resistance, coupled with the use of pathway analysis to rank predicted targets, has thus identified the activin/TGF-β signaling cascade as a potential target for overcoming resistance in AML.
化疗耐药是导致大多数急性髓系白血病（AML）相关死亡的根本原因，因此识别耐药通路成为当务之急。转录组学方法可用于识别在转录或mRNA稳定性层面受调控的基因，但会遗漏微小RNA（miRNA）介导的翻译水平变化，而这一机制已知在化疗耐药中发挥重要作用。为此，我们比较了HL60细胞中配对化疗敏感与耐药亚克隆的miRNA谱，并采用生物信息学方法预测受影响通路。在涉及的38条KEGG通路中，我们选择TGF-β/激活素家族信号通路进行深入研究。耐药HL60细胞表现出增强的TGF-β应答反应，但特异性抑制剂未能使其恢复化疗敏感性。随后，我们利用TGCA数据库中公开的基因表达数据，以及对有限病例耐药前后样本的纵向分析，在RNA水平研究了原发性AML样本中的通路差异表达。这证实了复发时TGF-β家族信号通路的表达与活性变化，并揭示诊断时TGF-β和激活素信号相关基因的表达与患者总生存期相关。本研究通过聚焦阿糖胞苷敏感与耐药的配对亚系来特异性识别耐药相关miRNA，结合通路分析对预测靶点进行排序，从而确定激活素/TGF-β信号级联反应可作为克服AML耐药性的潜在靶点。
MicroRNA Expression Patterns Reveal a Role of the TGF-β Family Signaling in AML Chemo-Resistance
肿瘤(癌症)患者之家