FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts

Abstract

Friend virus-induced erythroleukemia involves two members of the ETS family of transcriptional regulators, both activated via proviral insertion in the 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-MuLV helper virus in newborn mice. To analyse the consequences of the enforced expression of FLI-1 on erythroblast differentiation and proliferation and to compare its activity to that of PU.1/Spi-1, we used a heterologous system of avian primary erythroblasts previously described to study the cooperation between Spi-1/PU.1 and the other molecular alterations observed in SFFV-induced disease. FLI-1 was found: (i) to inhibit the apoptotic cell death program normally activated in erythroblasts following Epo deprivation; (ii) to inhibit the terminal differentiation program induced in these cells in response to Epo and; (iii) to induce their proliferation. However, in contrast to Spi-1/PU.1, the effects of FLI-1 on erythroblast, differentiation and proliferation did not require its cooperation with an abnormally activated form of the EpoR. Enhanced survival of FLI-1 expressing erythroblasts correlated with the upregulation of bcl2 expression. FLI-1 also prevented the rapid downregulation of cyclin D2 and D3 expression normally observed during Epo-induced differentiation and delayed the downregulation of several other genes involved in cell cycle or cell proliferation control. Our results show that overexpression of FLI-1 profoundly deregulates the normal balance between differentiation and proliferation in primary erythroblasts. Thus, the activation of FLI-1 expression observed at the onset of F-MuLV-induced erythroleukemia may provide a proliferative advantage to virus infected cells that would otherwise undergo terminal differentiation or cell death.

Epo regulates erythroid proliferation and differentiation through distinct signaling pathways: implication for erythropoiesis and Friend virus-induced erythroleukemia

“…Recently, a similar result was also reported in chicken erythroblasts transfected with Fli-1 (Pereira et al, 1999). Similarly, gp55 expression in HB60-5 cells conferred a growth advantage that was associated with elevated Fli-1 expression levels.…”

Overexpression of Ets-1 in human hematopoietic progenitor cells blocks erythroid and promotes megakaryocytic differentiation

“…In vitro differentiation studies have shown that in human hematopoietic cell lines, Fli-1 expression promotes MK 34 and suppresses erythroid differentiation. 35,36 The patterns of expression of Ets-1 and Fli-1 were shown to be similar, 28,37 and we found that during 'in vitro' erythroid and MK differentiation, Fli-1 expression profile was superimposable to that of Ets-1 (our unpublished data). Interestingly, the Ets-1 and Fli-1 genes are physically linked, located within 200 kb on human chromosome 11.…”

Friend Leukemia Virus Infection Enhances DNA Damage-Induced Apoptosis of Hematopoietic Cells, Causing Lethal Anemia in C3H Hosts

“…In FLV-induced leukemogenesis, the Spi-1 and Fli-1 genes of the host are known to be activated during oncogenesis. These molecules function as transcriptional factors in FLV-induced erythroid leukemic cells and usually inhibit apoptotic cell death in erythroblasts (28,30). However, overexpression of Spi-1 induced growth inhibition, differentiation inhibition, and apoptotic cell death in FLV-induced erythroleukemia cells (43).…”

“…In contrast, human immunodeficiency virus caused apoptosis in CD4 ϩ T cells via gp120 in combination with T cell receptorenhanced (1) and Moloney murine leukemia virus-enhanced thymocyte apoptosis (4). FLV infection usually causes antiapoptotic features in transformed cell lines (14,28,30) as well as in primary erythroblasts (28), although the early effect of FLV infection on apoptotic signaling is still uncertain.The DNA damage induced by gamma irradiation is known to cause p53-dependent apoptosis in many kinds of cells and tissues in vitro as well as in vivo (34). For the purpose of radiotherapy for FLV-induced disease, split low-dose totalbody irradiation (TBI) treatment with 1.5 Gy of gamma irradiation has been performed and shown to exhibit a curative effect on FLV-induced leukemogenesis in DBA mice (36, 37, …”

“…In contrast, human immunodeficiency virus caused apoptosis in CD4 ϩ T cells via gp120 in combination with T cell receptorenhanced (1) and Moloney murine leukemia virus-enhanced thymocyte apoptosis (4). FLV infection usually causes antiapoptotic features in transformed cell lines (14,28,30) as well as in primary erythroblasts (28), although the early effect of FLV infection on apoptotic signaling is still uncertain.…”