Kirschner Gyöngyi, Balla Bernadett, Horváth Péter, Kövesdi Andrea, Lakatos Gergely, Takács István, Nagy Zsolt, Tóbiás Bálint, Árvai Kristóf, Kósa János Pál, Lakatos Péter
First Department of Internal Medicine, Semmelweis University, 1083 Budapest, Hungary.
Second Department of Internal Medicine, Semmelweis University, 1083 Budapest, Hungary.
Mol Med Rep. 2016 Sep;14(3):2025-37. doi: 10.3892/mmr.2016.5459. Epub 2016 Jun 30.
Numerous clinical observations have confirmed that breakpoint cluster region-abelson fusion oncoprotein tyrosine kinase inhibitors used in leukemia treatment alter bone physiology in a complex manner. The aim of the present study was to analyze the whole transcriptome of cultured murine osteoblasts and determine the changes following treatment with imatinib and nilotinib using Sequencing by Oligonucleotide Ligation and Detection next generation RNA sequencing. This study also aimed to identify candidate signaling pathways and network regulators by multivariate Ingenuity Pathway Analysis. Based on the right-tailed Fisher's exact test, significantly altered pathways including upstream regulators were defined for each drug. The correlation between these pathways and bone metabolism was also examined. The preliminary results suggest the two drugs have different mechanisms of action on osteoblasts, and imatinib was shown to have a greater effect on gene expression. Data also indicated the potential role of a number of genes and signaling cascades that may contribute to identifying novel targets for the treatment of metabolic bone diseases.
大量临床观察证实，用于白血病治疗的断裂点簇集区-阿贝尔森融合癌蛋白酪氨酸激酶抑制剂会以复杂的方式改变骨骼生理。本研究的目的是分析培养的小鼠成骨细胞的全转录组，并使用寡核苷酸连接检测下一代RNA测序技术确定伊马替尼和尼洛替尼处理后的变化。本研究还旨在通过多变量 Ingenuity 通路分析识别候选信号通路和网络调节因子。基于右尾 Fisher 精确检验，为每种药物定义了包括上游调节因子在内的显著改变的通路。还研究了这些通路与骨代谢之间的相关性。初步结果表明这两种药物对成骨细胞具有不同的作用机制，并且伊马替尼对基因表达的影响更大。数据还表明许多基因和信号级联反应的潜在作用，这可能有助于识别代谢性骨病治疗的新靶点。
