FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts

Friend virus-induced erythroleukemia involves two members of the ETS family of transcriptional regulators, both activated via proviral insertion in th e corresponding loci. Spi-1/PU.1 is expressed in the disease induced by the original Friend virus SFFV(F-MuLV) complex in adult mice. In contrast, FLI -1 is overexpressed in about 75% of the erythroleukemias induced by the F-M uLV helper virus in newborn mice, To analyse the consequences of the enforc ed expression of FLI-1 on erythroblast differentiation and proliferation an d to compare its activity to that of PU.1/Spi-1, we used a heterologous sys tem of avian primary erythroblasts previously described to study the cooper ation between Spi-1/PU.1 and the other molecular alterations observed in SF FV-induced disease, FLI-1 was found: (i) to inhibit the apoptotic cell deat h program normally activated in erythroblasts following Epo deprivation; (i i) to inhibit the terminal differentiation program induced in these cells i n response to Epo and; (iii) to induce their proliferation, However, in con trast to Spi-1/PU.1, the effects of FLI-1 on erythroblast, differentiation and proliferation did not require its cooperation with an abnormally activa ted form of the EpoR, Enhanced survival of FLI-1 expressing erythroblasts c orrelated with the upregulation of bcl2 expression, FLI-1 also prevented th e rapid downregulation of cyclin D2 and D3 expression normally observed dur ing Epo-induced differentiation and delayed the downregulation of several o ther genes involved in cell cycle or cell proliferation control, Our result s show that overexpression of FLI-1 profoundly deregulates the normal balan ce between differentiation and proliferation in primary erythroblasts, Thus , the activation of FLI-1 expression observed at the onset of F-MuLV-induce d erythroleukemia may provide a proliferative advantage to virus infected c ells that would otherwise undergo terminal differentiation or cell death.