Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, India.
Department of Clinical Haematology, SCB Medical College, Cuttack, Odisha, India.
Sci Rep. 2016 Sep 2;6:32493. doi: 10.1038/srep32493.
Chronic myeloid leukemia (CML) is maintained by leukemic stem cells (LSCs) which are resistant to the existing TKI therapy. Hence a better understanding of the CML LSCs is necessary to eradicate these cells and achieve complete cure. Using the miRNA-gene interaction networks from the CML lin(-) cells we identified a set of up/down-regulated miRNAs and corresponding target genes. Association studies (Pearson correlation) from the miRNA and gene expression data showed that miR-1469 and miR-1972 have significantly higher number of target genes, 75 and 50 respectively. We observed that miR-1972 induces G2-M cell cycle arrest and miR-1469 moderately arrested G1 cell cycle when overexpressed in KCL22 cells. We have earlier shown that a combination of imatinib and JAK inhibitor I can significantly bring down the proliferation of CML lineage negative cells. Here we observed that imatinib and JAK inhibitor I combination restored the expression pattern of the down-regulated miRNAs in primary CML lin(-) cells. Thus effective manipulation of the deregulated miRNAs can restore the miRNA-mRNA networks that can efficiently inhibit CML stem and progenitor cells and alleviate the disease.
慢性髓性白血病（CML）由白血病干细胞（LSCs）维持，这些细胞对现有的 TKI 治疗具有抗性。因此，需要更好地了解 CML LSCs，以消灭这些细胞并实现完全治愈。我们使用来自 CML lin(-)细胞的 miRNA-基因相互作用网络，鉴定了一组上调/下调的 miRNA 和相应的靶基因。miRNA 和基因表达数据的关联研究（Pearson 相关性）表明，miR-1469 和 miR-1972 分别具有显著更多的靶基因，分别为 75 和 50 个。我们观察到，当在 KCL22 细胞中过表达时，miR-1972 诱导 G2-M 细胞周期停滞，而 miR-1469 适度地停滞 G1 细胞周期。我们之前已经表明，伊马替尼和 JAK 抑制剂 I 的组合可以显著降低 CML 谱系阴性细胞的增殖。在这里，我们观察到伊马替尼和 JAK 抑制剂 I 的组合恢复了原发性 CML lin(-)细胞中下调的 miRNA 的表达模式。因此，有效操纵失调的 miRNA 可以恢复 miRNA-mRNA 网络，有效地抑制 CML 干细胞和祖细胞，并减轻疾病。
