Regulation of the expression of the oncogene EVI1 through the use of alternative mRNA 5′-ends

Aytekin, Metin; Vinatzer, Ursula; Musteanu, Mónica; Raynaud, Sophie; Wieser, Rotraud

doi:10.1016/j.gene.2005.04.032

Cited by 33 publications

(42 citation statements)

References 29 publications

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“…Our own previous studies have shown that EVI1 was not only regulated by ATRA through direct binding of the retinoic acid receptor heterodimer to a canonical RARE located in the most 5' one of several alternative first exons, 50,62 but that EVI1 in turn modulated ATRA regulated transcription: it counteracted its own induction by ATRA in a negative feedback loop, but augmented the ATRA induction of the RARb gene. 50 Based on these findings, we now asked whether EVI1 would modulate the regulation by ATRA of a larger number of genes, and whether it would also impact on biological responses to ATRA.…”

Section: Introductionmentioning

confidence: 92%

The oncogeneEVI1enhances transcriptional and biological responses of human myeloid cells toall-transretinoic acid

Steinmetz¹,

Hackl²,

Slabáková³

et al. 2014

Cell Cycle

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The product of the ecotropic virus integration site 1 (EVI1) gene, whose overexpression is associated with a poor prognosis in myeloid leukemias and some epithelial tumors, regulates gene transcription both through direct DNA binding and through modulation of the activity of other sequence specific transcription factors. Previous results from our laboratory have shown that EVI1 influenced transcription regulation in response to the myeloid differentiation inducing agent, all-trans retinoic acid (ATRA), in a dual manner: it enhanced ATRA induced transcription of the RARb gene, but repressed the ATRA induction of the EVI1 gene itself. In the present study, we asked whether EVI1 would modulate the ATRA regulation of a larger number of genes, as well as biological responses to this agent, in human myeloid cells. U937 and HL-60 cells ectopically expressing EVI1 through retroviral transduction were subjected to microarray based gene expression analysis, and to assays measuring cellular proliferation, differentiation, and apoptosis. These experiments showed that EVI1 modulated the ATRA response of several dozens of genes, and in fact reinforced it in the vast majority of cases. A particularly strong synergy between EVI1 and ATRA was observed for GDF15, which codes for a member of the TGF-b superfamily of cytokines. In line with the gene expression results, EVI1 enhanced cell cycle arrest, differentiation, and apoptosis in response to ATRA, and knockdown of GDF15 counteracted some of these effects. The potential clinical implications of these findings are discussed.

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Section: Introductionmentioning

confidence: 92%

The oncogeneEVI1enhances transcriptional and biological responses of human myeloid cells toall-transretinoic acid

Steinmetz¹,

Hackl²,

Slabáková³

et al. 2014

Cell Cycle

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“…3,5,13 EVI1-1D splice form and ME expression levels were determined using probes, 3 whereas the other EVI1 splice variants 5 (-1A, -1B, -1C, and -3L) were analyzed using SYBR green (Applied Biosystems, Foster City, CA). A systematic overview of the EVI1 splice forms and the primer/probe localizations are shown in Figure 1.…”

Section: Real-time Quantitative Pcr and Northern Blot Analysesmentioning

confidence: 99%

“…3,4 High expression of EVI1 (ie, splice form EVI1-1D) is an independent negative prognostic indicator of survival in AML irrespective of the presence of 3q26 rearrangements. 3 At least 4 additional splice variants of EVI1 were recently identified (ie, EVI1-1A, -1B, -1C, and -3L 5 ), differing mainly in their 5Ј untranslated regions. Since, we previously determined only the relative expression of EVI1-1D, 3 it is feasible that EVI1 ϩ AML cases have been underestimated.…”

Section: Introductionmentioning

confidence: 99%

High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated

Lugthart¹,

Drunen

Norden

et al. 2008

Blood

251

246

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Inappropriate expression of EVI1 (ecotropic virus integration-1), in particular splice form EVI1-1D, through chromosome 3q26 lesions or other mechanisms has been implicated in the development of high-risk acute myeloid leukemia (AML). To validate the clinical relevance of EVI1-1D, as well as of the other EVI1 splice forms and the related MDS1/EVI1 (ME) gene, real-time quantitative polymerase chain reaction was performed in 534 untreated adults with de novo AML. EVI1-1D was highly expressed in 6% of cases (n ‫؍‬ 32), whereas 7.8% were EVI1 ؉ (n ‫؍‬ 41) when all splice variants were taken into account. High EVI1 predicted a distinctly worse event-free survival (HR ‫؍‬ 1.9; P ‫؍‬ .002) and disease-free survival (HR ‫؍‬ 2.1, P ‫؍‬ .006) following multivariate analysis. Importantly, we distinguished a subset of EVI1 ؉ cases that lacked expression of ME (EVI1 ϩ ME Ϫ ; n ‫؍‬ 17) from cases that were ME ؉ (EVI1 ϩ ME ϩ ; n ‫؍‬ 24). The atypical EVI1 ϩ ME Ϫ expression pattern exhibited cytogenetically detectable chromosomal 3q26 breakpoints in 8 cases. Fluorescence in situ hybridization revealed 7 more EVI1 ϩ ME Ϫ cases that carried cryptic 3q26 breakpoints, which were not found in the EVI1 ϩ ME ϩ group. EVI1 ϩ ME Ϫ expression predicts an extremely poor prognosis distinguishable from the general EVI1 ϩ AML patients (overall survival

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“…1,6 Although the EVI1 function is not fully understood, recent studies suggest that this gene is involved in chromatin remodeling, through interactions with H3K9 methyltransferases 7,8 Five splice variants of EVI1 have been reported, that is EVI1-1A, -1B, -1C, -1D, and -3L, as well as the MDS1/EVI1 intergenic splice variant. 9,10 The MDS1 gene is located upstream of EVI1 and its function is currently unknown. In the MDS1/EVI1 transcripts, the first two exons of MDS1 have been fused to exon 2 of EVI1, resulting in a so-called PR domain containing the EVI1 protein.…”

Section: Introductionmentioning

confidence: 99%

EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia

et al. 2010

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Overexpression of the ecotropic virus integration-1 (EVI1) gene (EVI1 þ ), localized at chromosome 3q26, is associated with adverse outcome in adult acute myeloid leukemia (AML). In pediatric AML, 3q26 abnormalities are rare, and the role of EVI1 is unknown. We studied 228 pediatric AML samples for EVI1 þ using gene expression profiling and RQ-PCR. EVI1 þ was found in 20/213 (9%) of children with de novo AML, and in 4/8 with secondary AML. It was predominantly found in MLLrearranged AML (13/47), monosomy 7 (2/3), or FAB M6/7 (6/10), and mutually exclusive with core-binding factor AML, t(15;17), and NPM1 mutations. Fluorescent in situ hybridization (FISH) was performed to detect cryptic 3q26 abnormalities. However, none of the EVI1 þ patients harbored structural 3q26 alterations. Although significant differences in 4 years pEFS for EVI1 þ and EVI1À pediatric AML were observed (28%±11 vs 44%±4, P ¼ 0.04), multivariate analysis did not identify EVI1 þ as an independent prognostic factor. We conclude that EVI1 þ can be found in B10% of pediatric AML. Although EVI1 þ was not an independent prognostic factor, it was predominantly found in subtypes of pediatric AML that are related with an intermediate to unfavorable prognosis. Further research should explain the role of EVI1 þ in disease biology in these cases. Remarkably, no 3q26 abnormalities were identified in EVI1 þ pediatric AML.

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Regulation of the expression of the oncogene EVI1 through the use of alternative mRNA 5′-ends

Cited by 33 publications

References 29 publications

The oncogeneEVI1enhances transcriptional and biological responses of human myeloid cells toall-transretinoic acid

The oncogeneEVI1enhances transcriptional and biological responses of human myeloid cells toall-transretinoic acid

High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated

EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia

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