Bone Marrow Transplantation Center, The First Affiliated Hospital, Medical School of Zhejiang University, Hangzhou 310003, P.R. China.
Zhejiang Cancer Hospital, Hangzhou 310022, P.R. China.
Int J Oncol. 2015 Jan;46(1):351-9. doi: 10.3892/ijo.2014.2738. Epub 2014 Oct 30.
Recent developments and re-emergence of interferon α (IFN-α) have renewed interest in the therapy for patients with chronic myeloid leukemia (CML). Related molecular mechanism may be the direct effect of IFN-α on CML stem cells. Human mesenchymal stromal cells (hMSCs) are important to protect CML stem cells, and IFN-α was described as a potential inhibitor of hMSCs. However, the exact mechanism remains obscure. PML as a known tumor suppressor locates downstream of the IFN-α pathway, and little is known about the PML gene regulation in hMSCs. The aim of this study was to investigate the effects of IFN-α on hMSCs and defined the role of PML involved in this process. Our results suggested that hMSCs incurred senescence upon IFN-α stimulation, while PML levels were observed significant increased. The recombinant lentiviral vector, which encodes shRNA against PML or full-length PML cDNA, was constructed. By knocking-down and overexpressing PML, we found that PML was indispensable to IFN-α mediated hMSC senescence. The molecular mechanism underlying this process may be an increased co-localization of PML and p53 induced by IFN-α. Our data demonstrated that IFN-α can induce cellular senescence of hMSCs and PML plays a key role in this process. These findings provided novel insight into the effect of IFN-α on hMSCs.
干扰素 α（IFN-α）的最新进展和再次出现重新引起了人们对慢性髓系白血病（CML）患者治疗的兴趣。相关的分子机制可能是 IFN-α对 CML 干细胞的直接作用。人间质基质细胞（hMSC）对于保护 CML 干细胞很重要，IFN-α被描述为 hMSC 的潜在抑制剂。然而，确切的机制仍不清楚。PML 作为已知的肿瘤抑制因子，位于 IFN-α通路的下游，关于 PML 基因在 hMSC 中的调控知之甚少。本研究旨在探讨 IFN-α对 hMSC 的影响，并确定 PML 在该过程中所涉及的作用。我们的结果表明，IFN-α刺激 hMSC 衰老，而 PML 水平明显增加。构建了编码针对 PML 的 shRNA 或全长 PML cDNA 的重组慢病毒载体。通过敲低和过表达 PML，我们发现 PML 对于 IFN-α 介导的 hMSC 衰老至关重要。该过程的分子机制可能是 IFN-α诱导的 PML 和 p53 的共定位增加。我们的数据表明，IFN-α可诱导 hMSC 细胞衰老，而 PML 在该过程中起关键作用。这些发现为 IFN-α对 hMSC 的影响提供了新的见解。
