Amplification of MDS1/EVI1 and EVI1, Located in the 3q26.2 Amplicon, Is Associated with Favorable Patient Prognosis in Ovarian Cancer

Nanjundan, Meera; Nakayama, Yasuhisa; Cheng, Kwai Wa; Lahad, John; Liu, Jinsong; Lu, Karen W.; Kuo, Wen-Lin; Smith‐McCune, Karen; Fishman, David A.; Gray, Joe W.; Mills, Gordon B.

doi:10.1158/0008-5472.can-06-2366

Cited by 113 publications

(162 citation statements)

References 43 publications

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“…4C), consistent with EVI1's known function as a critical regulator of embryonic development (12,32). We also found marked enrichment for genes controlling processes formerly associated with EVI1 (10,12,33), including apoptosis, cell proliferation, and migration. Interestingly, several potential biological functions were associated with EVI1 target genes, including cell adhesion, cell metabolism, response to oxidative stress, cell structure, and motility.…”

Section: Resultssupporting

confidence: 80%

“…Collectively, our data indicate that EVI1 is a multipurpose transcription factor that synergizes with FOS in invasive tumors. E cotropic viral integration site 1 (EVI1) is a zinc finger (ZNF) transcription factor (TF), and its overexpression in myeloid leukemia (1)(2)(3) and epithelial cancers (1,2,(4)(5)(6)(7)(8)(9) has been extensively studied and correlated with adverse patient outcome (7,10,11). EVI1 also controls several aspects of embryonic development, including hematopoiesis, angiogenesis, and heart and neural development (12).…”

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confidence: 99%

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Ecotopic viral integration site 1 (EVI1) regulates multiple cellular processes important for cancer and is a synergistic partner for FOS protein in invasive tumors

Bard-Chapeau

Jeyakani

Kok

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

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Ecotropic viral integration site 1 (EVI1) is an oncogenic dual domain zinc finger transcription factor that plays an essential role in the regulation of hematopoietic stem cell renewal, and its overexpression in myeloid leukemia and epithelial cancers is associated with poor patient survival. Despite the discovery of EVI1 in 1988 and its emerging role as a dominant oncogene in various types of cancer, few EVI1 target genes are known. This lack of knowledge has precluded a clear understanding of exactly how EVI1 contributes to cancer. Using a combination of ChIP-Seq and microarray studies in human ovarian carcinoma cells, we show that the two zinc finger domains of EVI1 bind to DNA independently and regulate different sets of target genes. Strikingly, an enriched fraction of EVI1 target genes are cancer genes or genes associated with cancer. We also show that more than 25% of EVI1-occupied genes contain linked EVI1 and activator protein (AP)1 DNA binding sites, and this finding provides evidence for a synergistic cooperative interaction between EVI1 and the AP1 family member FOS in the regulation of cell adhesion, proliferation, and colony formation. An increased number of dual EVI1/AP1 target genes are also differentially regulated in late-stage ovarian carcinomas, further confirming the importance of the functional cooperation between EVI1 and FOS. Collectively, our data indicate that EVI1 is a multipurpose transcription factor that synergizes with FOS in invasive tumors. E cotropic viral integration site 1 (EVI1) is a zinc finger (ZNF) transcription factor (TF), and its overexpression in myeloid leukemia (1-3) and epithelial cancers (1, 2, 4-9) has been extensively studied and correlated with adverse patient outcome (7, 10, 11). EVI1 also controls several aspects of embryonic development, including hematopoiesis, angiogenesis, and heart and neural development (12). Three major alternative splice forms of the MDS1 and EVI1 complex locus (MECOM) locus have been identified, including EVI1, EVI1Δ324, and MDS1-EVI1. The PRDI-BF1 and RIZ homology domain containing Myelodysplastic syndrome (MDS)1-EVI1 isoform acts as a tumor suppressor gene, whereas the shorter isoforms, EVI1 and EVI1Δ324, that lack this domain display oncogenic functions (13). The most oncogenic isoform, EVI1, encodes a 1,051-aa protein containing two DNA binding ZNF domains of seven and three motifs. The N-terminal ZNF domain binds to a GATA-like consensus motif (14), whereas the distal ZNF domain binds to an v-ets erythroblastosis virus E26 oncogene homolog (ETS)-like motif (15). EVI1Δ324 lacks ZNFs motifs 6 and 7, which prevents its binding to GATA-like sites.Despite its discovery in 1988 (16, 17), very few EVI1 target genes have been identified, and most of these loci are known to be bound by EVI1 . This lack of knowledge regarding the genes transcriptionally regulated by EVI1 has precluded a complete understanding of EVI1's role in development and cancer. In general, these biological processes are triggered by gene expression changes coordinate...

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Section: Resultssupporting

confidence: 80%

mentioning

confidence: 99%

Ecotopic viral integration site 1 (EVI1) regulates multiple cellular processes important for cancer and is a synergistic partner for FOS protein in invasive tumors

Bard-Chapeau

Jeyakani

Kok

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

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“…Several reports in the literature lend support to the thesis of ''multiple driver genes'' per amplicon. Amplicons that have been shown functionally involving multiple driver genes include the 11q22 amplicon in liver cancer (40), the HER2 amplicon (41), and the 8p11-12 amplicon (42) in breast cancer, the 3q26.2 amplicon in ovarian cancer (43), and finally the 19q13 amplicon in pancreatic cancer (44). Based on our findings, the focal point of this study, 14q13.3 amplicon, is very likely to also involve multiple coamplified driver genes.…”

Section: Discussionmentioning

confidence: 61%

Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer

Kendall

Liu

Bakleh

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

204

213

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We used high-resolution array analysis to discover a recurrent lung cancer amplicon located at 14q13.3. Low-level gain of this region was detected in 15% of lung cancer samples, and high-level amplification was detected in an additional 4% of samples. Highlevel focal amplification appears to be specific to lung cancers, because it was not detected in >500 samples of other tumor types. Mapping of the commonly amplified region revealed there are three genes in the core region, all of which encode transcription factors with either established lung developmental function (TTF1/ NKX2-1, NKX2-8) or potential lung developmental function (PAX9). All three genes were overexpressed to varying degrees in amplified samples, although TTF1/NKX2-1 was not expressed in the squamous cancer subtype, consistent with previous reports. Remarkably, overexpression of any pairwise combination of these genes showed pronounced synergy in promoting the proliferation of immortalized human lung epithelial cells. Analysis of human lung cancer cell lines by both RNAi and ectopic overexpression further substantiates an oncogenic role for these transcription factors. These results, taken together with previous reports of oncogenic alterations of transcription factors involved in lung development (p63, CEBPA), suggest genetic alterations that directly interfere with transcriptional networks normally regulating lung development may be a more common feature of lung cancer than previously realized.gene amplification ͉ lung development ͉ lung oncogene ͉ TTF1 NKX2-8 PAX9 ͉ lineage addiction

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“…Many studies have demonstrated the significance of the cytoplasmic membranous expression of CD24 in the prediction of the prognosis of ovarian cancer patients (31)(32)(33)(34)(35). Protein levels of EVI1 and MDS1 were reported to be increased in both ovarian cancer tissues and ovarian cancer cell lines (36). Nanjundan et al (36) recently revealed that DNA copy number increases of both genes were associated with at least 5-fold-increased RNA transcript levels in 83 and 98% of advanced ovarian cancer cases, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Protein levels of EVI1 and MDS1 were reported to be increased in both ovarian cancer tissues and ovarian cancer cell lines (36). Nanjundan et al (36) recently revealed that DNA copy number increases of both genes were associated with at least 5-fold-increased RNA transcript levels in 83 and 98% of advanced ovarian cancer cases, respectively. The high expression level of homeobox member gene HOXB7 mRNA reveals its possible involvement in the invasive characteristics of ovarian cancer cells (37,38).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide gene expression profiles of ovarian carcinoma: Identification of molecular targets for the treatment of ovarian carcinoma

Nikolova

Doganov²,

Dimitrov³

et al. 2009

Mol Med Rep

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Abstract. This study aimed to clarify the molecular mechanisms involved in ovarian carcinogenesis, and to identify candidate molecular targets for its diagnosis and treatment. The genome-wide gene expression profiles of 22 epithelial ovarian carcinomas were analyzed with a microarray representing 38,500 genes, in combination with laser microbeam microdissection. A total of 273 commonly up-regulated transcripts and 387 down-regulated transcripts were identified in the ovarian carcinoma samples. Of the 273 up-regulated transcripts, only 87 (31.9%) were previously reported as upregulated in microarray studies using bulk cancer tissues and normal ovarian tissues for analysis. CHMP4C (chromatinmodifying protein 4C) was frequently overexpressed in ovarian carcinoma tissue, but not expressed in the normal human tissues used as a control. Our data should contribute to an improved understanding of tumorigenesis in ovarian cancer, and aid in the development of diagnostic tumor markers and molecular-targeting therapy for patients with the disease.

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Amplification of MDS1/EVI1 and EVI1, Located in the 3q26.2 Amplicon, Is Associated with Favorable Patient Prognosis in Ovarian Cancer

Cited by 113 publications

References 43 publications

Ecotopic viral integration site 1 (EVI1) regulates multiple cellular processes important for cancer and is a synergistic partner for FOS protein in invasive tumors

Ecotopic viral integration site 1 (EVI1) regulates multiple cellular processes important for cancer and is a synergistic partner for FOS protein in invasive tumors

Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer

Genome-wide gene expression profiles of ovarian carcinoma: Identification of molecular targets for the treatment of ovarian carcinoma

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