Spi-1, Fli-1 and Fli-3 (miR-17-92) Oncogenes Contribute to a Single Oncogenic Network Controlling Cell Proliferation in Friend Erythroleukemia

Clonal erythroleukemia developing in susceptible mice infected by Friend virus complex are associated with highly recurrent proviral insertions at one of three loci called Spi-1, Fli-1 or Fli-3, leading to deregulated expression of oncogenic Spi-1 or Fli-1 transcription factors or miR-17-92 miRNA cluster, respectively. Deregulated expression of each of these three oncogenes has been independently shown to contribute to cell proliferation of erythroleukemic clones. Previous studies showed a close relationship between Spi-1 and Fli-1, which belong to the same ETS family, Spi-1 activating fli-1 gene, and both Spi-1 and Fli-1 activating multiple common target genes involved in ribosome biogenesis. In this study, we demonstrated that Spi-1 and Fli-1 are also involved in direct miR-17-92 transcriptional activation through their binding to a conserved ETS binding site in its promoter. Moreover, we demonstrated that physiological re-expression of exogenous miR-17 and miR-20a are able to partially rescue the proliferation loss induced by Fli-1 knock-down and identified HBP1 as a target of these miRNA in erythroleukemic cells. These results establish that three of the most recurrently activated oncogenes in Friend erythroleukemia are actually involved in a same oncogenic network controlling cell proliferation. The putative contribution of a similar ETS-miR-17-92 network module in other normal or pathological proliferative contexts is discussed.感染弗氏病毒复合体（Friend virus complex）的易感小鼠所发生的克隆性红白血病，与三个名为Spi-1、Fli-1或Fli-3的基因座（loci）上频发的前病毒插入（proviral insertions）高度相关，该类插入可分别引发致癌性Spi-1或Fli-1转录因子、miR-17-92 microRNA簇（miR-17-92 miRNA cluster）的表达失调。 现有研究已独立证实，这三种致癌基因各自的表达失调均可促进红白血病克隆的细胞增殖。既往研究显示，同属ETS家族（ETS family）的Spi-1与Fli-1之间存在密切关联：Spi-1可激活fli-1基因，且二者均可激活参与核糖体生物发生的多种共同靶基因。 本研究证实，Spi-1与Fli-1还可通过结合miR-17-92启动子区域内的保守ETS结合位点（ETS binding site），直接介导该microRNA簇的转录激活。此外，本研究证明，外源性（exogenous）miR-17与miR-20a恢复至生理水平的表达后，可部分挽救Fli-1基因敲低（knock-down）诱导的增殖缺陷，并鉴定出HBP1是这些microRNA在红白血病细胞中的靶基因。 上述结果证实，弗氏红白血病中三种最常被激活的致癌基因，实则共同参与了调控细胞增殖的同一致癌网络。本文还讨论了类似的ETS-miR-17-92网络模块在其他正常或病理增殖场景中的潜在作用。