Evi1 is a myeloid-specific protooncogene that encodes 145 kDa and 88 kDa proteins via alternative splicing. Overexpression of the gene via retroviral insertion in murine tumors or chromosomal rearrangement in human tumors is associated with myeloid leukemias and myelodysplasias; however, the mechanism by which such overexpression leads to transformation is not clear. It has been postulated that overexpression of evi1 acts to block normal myelopoiesis. In attempts to assess the effect of overexpression of evi1 on myelopoiesis, we chose to utilize the IL-3-dependent murine 32Dcl3 cell line, which has been shown to differentiate in culture in response to G-CSF. Previous experiments with this cell line, which we have confirmed, showed that overexpression of evi1, mediated by retroviral vector transfer, caused a block to G-CSF-induced cell survival and differentiation. We report here that the naive 32Dcl3 cell line contains a rearrangement of the evi1 locus and constitutively overexpresses evi1 mRNA and protein; this expression is downregulated only slightly during G-CSF-induced myeloid maturation. The steady state levels, molecular weight and DNA binding characteristics of the EVI1 protein in these cells is comparable to that seen in NFS 58, a myeloid leukemia cell line with retroviral insertion at evi1. The observed ability of the murine 32Dcl3 cells to fully differentiate in the presence of G-CSF while evi1 continues to be expressed indicates that, at the levels expressed in naive 32Dcl3, evi1 does not block G-CSF-induced survival and differentiation. Thus, retroviral insertions at evi1 may have been selected for in 32Dcl3 cells due to effects other than that on G-CSF-induced cell survival.
"Morishita et al first reported Evi1 overexpression in 32Dc13 myeloid cells inhibits terminal differentiation to granulocytes in response to granulocyte-colony stimulating factor (G-CSF) . However it was later shown that native 32Dc13 cells harbor a proviral insertion at Evi1 and overexpress both mRNA and protein . In addition, this assay is difficult to interpret, since the EVI1-overexpressing cells undergo cell death upon treatment with G-CSF. "
[Show abstract][Hide abstract] ABSTRACT: The ecotropic virus integration site 1 (EVI1) transcription factor is associated with human myeloid malignancy of poor prognosis and is overexpressed in 8-10% of adult AML and strikingly up to 27% of pediatric MLL-rearranged leukemias. For the first time, we report comprehensive genomewide EVI1 binding and whole transcriptome gene deregulation in leukemic cells using a combination of ChIP-Seq and RNA-Seq expression profiling. We found disruption of terminal myeloid differentiation and cell cycle regulation to be prominent in EVI-induced leukemogenesis. Specifically, we identified EVI1 directly binds to and downregulates the master myeloid differentiation gene Cebpe and several of its downstream gene targets critical for terminal myeloid differentiation. We also found EVI1 binds to and downregulates Serpinb2 as well as numerous genes involved in the Jak-Stat signaling pathway. Finally, we identified decreased expression of several ATP-dependent P2X purinoreceptors genes involved in apoptosis mechanisms. These findings provide a foundation for future study of potential therapeutic gene targets for EVI1-induced leukemia.
PLoS ONE 06/2013; 8(6):e67134. DOI:10.1371/journal.pone.0067134 · 3.23 Impact Factor
"Furthermore, EVI-1 may inhibit GATA-1-dependent erythroid differentiation (Kreider et al, 1993; Louz et al, 2000), as well as myeloid differentiation of 32Dc13 cells (Morishita et al, 1992b). However, contradictory results have also been presented (Khanna Gupta et al, 1996; Fontenay Roupie et al, 1997). More recently, an alternative form of EVI-1, MDS1/EVI1, has been described (Fears et al, 1996; Wimmer et al, 1998). "
[Show abstract][Hide abstract] ABSTRACT: EVI-1 and its variant form, MDS1/EVI1, have been reported to act in an antagonistic manner and be differentially regulated in samples from patients with acute myeloid leukaemia and rearrangements of the long arm of chromosome 3. Here, we show that both EVI-1 and MDS1/EVI1 can repress transcription from a reporter construct containing EVI-1 binding sites and interact with histone deacetylase in mammalian cells. This interaction can be recapitulated in vitro and is mediated by a previously characterized transcription repression domain, whose activity is alleviated by the histone deacetylase inhibitor trichostatin A.
British Journal of Haematology 08/2001; 114(3):566 - 573. DOI:10.1046/j.1365-2141.2001.02987.x · 4.71 Impact Factor
"As the ribophorin 1 gene is located near to and telomeric of thèbreakpoint cluster region', it has been suggested that its enhancer might be responsible for the activation of the EVI-1 gene in 3q26 in cases with inv(3)(q21q26) or t(3;3)(q21;q26) (Suzukawa et al, 1994). EVI-1 codes for a zinc finger transcription factor which has been shown to be able to inhibit myeloid differentiation (Morishita et al, 1992; Kreider et al, 1993 but see also Khanna Gupta et al, 1996; Fontenay Roupie et al, 1997). However, its possible physiological functions in haematopoiesis as well as its transcriptional targets remain to be elucidated. "
[Show abstract][Hide abstract] ABSTRACT: Chromosome aberrations affecting band 3q21 are associated with a particularly poor prognosis in patients with acute myeloid leukaemia. To facilitate the molecular characterization of such rearrangements, we established a PAC contig covering the relevant genomic region. Using these PACs as probes in fluorescence in situ hybridization (FISH) experiments, we showed that a number of 3q21 breakpoints in patient samples map to a previously defined ‘breakpoint cluster region’. Others, however, are located at varying distances centromeric of it. These results have important implications in the search for genes affected by 3q21 rearrangements.
British Journal of Haematology 07/2000; 110(2):343 - 350. DOI:10.1046/j.1365-2141.2000.02192.x · 4.71 Impact Factor
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