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.