Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ecotropic viral integration site 1 (EVI1) gene was identified as a common locus of retroviral integration in myeloid tumors found in mice. EVI1 gene is highly conserved through evolution and human gene EVI1 on chromosome 3q26 encodes zinc fingers-containing transcription factor. EVI1 is expressed in nonhematopoietic tissues but not in normal blood or bone marrow. EVI1 was detected in hematopoietic cells in retrovirus-induced myeloid leukemias in mice and several reports documented EVI1 expression in human myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations. EVI1 is abnormally expressed in human myeloid leukemias that are associated with the t(3;3)(q21;q26), t(3;21)(q26;q22), inv(3)(q21q26) and other chromosomal rearrangements. EVI1 is overexpressed in some ovarian cancers and human colon cancer cell lines and may play a role in the initiation and/or progression of solid tumors, as well as hematopoietic malignancies. EVI1 is a transcriptional repressor which inhibits transforming growth factor beta (TGFbeta) family signalling by binding signal transducers (Smad proteins) and recruiting transcriptional corepressors. TGFbeta is an important regulator of proliferation, differentiation, apoptosis and migration of cells. EVI1 inhibits TGFbeta-mediated apoptosis. Knockdown of EVI1 function by small interference RNA increases the sensitivity of malignant cells to TGFbeta-mediated or other inducer-mediated apoptosis. Overexpressed EVI-1 blocks granulocyte and erythroid differentiation and possess the ability of growth promotion in some types of cells. EVI1 functions in some cases as a transcriptional activator which stimulates for example GATA2 and GATA3 promoters. The study of EVI1 target genes will help to clear the mechanism by which EVI1 upregulates cell proliferation, impairs cell differentiation, and induces cell transformation.
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PMID:[EVI1 and its role in myelodysplastic syndrome, myeloid leukemia and other malignant diseases]. 1699 17

The transcription factor ecotropic viral integration site 1 (Evi1) is associated with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients due to chromosomal aberration of chromosome 3. Here we show that Evi1 interacts with the histone methyltransferase SUV39H1. The interaction requires the N-terminal part of Evi1 and the H3-specific histone methyltransferase domain, SET, of SUV39H1 without Evi1 having an inhibitory effect on SUV39H1 methyltransferase activity. Presence of SUV39H1 enhances Evi1 transcriptional repression in a dose dependent manner. In addition, Evi1 also interacts with another histone methyltransferase, G9a, but not with SET9. Our data establish an epigenetic role of Evi1 in cell transformation by recruiting higher order chromatin remodeling complexes.
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PMID:A novel interaction between the proto-oncogene Evi1 and histone methyltransferases, SUV39H1 and G9a. 1861 62

The oncogene EVI1 has been implicated in the etiology of AML and MDS. Although AML cells are characterized by accelerated proliferation and differentiation arrest, MDS cells hyperproliferate when immature but fail to differentiate later and die instead. In agreement with its roles in AML and in immature MDS cells, EVI1 was found to stimulate cell proliferation and inhibit differentiation in several experimental systems. In contrast, the variant protein MDS1/EVI1 caused the opposite effect in some of these assays. In the present study, we expressed EVI1 and MDS1/EVI1 in a tetracycline-regulable manner in the human myeloid cell line U937. Induction of either of these proteins caused cells to accumulate in the G(0)/G(1)-phase of the cell cycle and moderately increased the rate of spontaneous apoptosis. However, when EVI1- or MDS1/EVI1-expressing cells were induced to differentiate, they massively succumbed to apoptosis, as reflected by the accumulation of phosphatidylserine in the outer leaflet of the plasma membrane and increased rates of DNA fragmentation. In summary, these data show that inducible expression of EVI1 in U937 cells causes phenotypes that may be relevant for its role in MDS and provides a basis for further investigation of its contribution to this fatal disease.
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PMID:Inducible expression of EVI1 in human myeloid cells causes phenotypes consistent with its role in myelodysplastic syndromes. 1960

Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.
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PMID:Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. 2013 68

Inv(3)(q21q26)/t(3;3)(q21;q26) is recognized as a distinctive entity of acute myeloid leukemia (AML) with recurrent genetic abnormalities of prognostic significance. It occurs in 1-2.5% of AML and is also observed in myelodysplastic syndromes and in the blastic phase of chronic myeloid leukemia. The molecular consequence of the inv(3)/t(3;3) rearrangements is the juxtaposition of the ribophorin I (RPN1) gene (located in band 3q21) with the ecotropic viral integration site 1 (EVI1) gene (located in band 3q26.2). Following conventional cytogenetics to determine the karyotype, fluorescent in situ hybridization (FISH) with a panel of bacterial artificial chromosome clones was used to map the breakpoints involved in 15 inv(3)/t(3;3). Inv(3) or t(3;3) was the sole karyotypic anomaly in 6 patients, while additional abnormalities were identified in the remaining 9 patients, including 4 with monosomy of chromosome7 (-7) or a deletion of its long arm (7q-). Breakpoints in band 3q21 were distributed in a 235 kb region centromeric to and including the RPN1 locus, while those in band 3q26.2 were scattered in a 900 kb region located on each side of and including the EVI1 locus. In contrast to most of the inversions and translocations associated with AML that lead to fusion genes, inv(3)/t(3;3) does not generate a chimeric gene, but rather induces gene overexpression. The wide dispersion of the breakpoints in bands 3q21 and 3q26 and the heterogeneity of the genomic consequences could explain why the mechanisms leading to leukemogenesis are still poorly understood. Therefore, it is important to further characterize these chromosomal abnormalities by FISH.
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PMID:Conventional cytogenetics and breakpoint distribution by fluorescent in situ hybridization in patients with malignant hemopathies associated with inv(3)(q21;q26) and t(3;3)(q21;q26). 2196 59

We report on a series of sequential events leading to long-term survival and cure of pediatric X-linked chronic granulomatous disease (X-CGD) patients after gamma-retroviral gene therapy (GT) and rescue HSCT. Due to therapyrefractory life-threatening infections requiring hematopoietic stem cell transplantation (HSCT) but absence of HLAidentical donors, we treated 2 boys with X-CGD by GT. Following GT both children completely resolved invasive Aspergillus nidulans infections. However, one child developed dual insertional activation of ecotropic viral integration site 1 (EVI1) and signal transducer and activator of transcription 3 (STAT3) genes, leading to myelodysplastic syndrome (MDS) with monosomy 7. Despite resistance to mismatched allo-HSCT with standard myeloablative conditioning, secondary intensified rescue allo-HSCT resulted in 100 % donor chimerism and disappearance of MDS. The other child did not develop MDS despite expansion of a clone with a single insertion in the myelodysplasia syndrome 1 (MDS1) gene and was cured by early standard allo-HSCT. The slowly developing dominance of clones harboring integrations in MDS1-EVI1 may guide clinical intervention strategies, i.e. early rescue allo-HSCT, prior to malignant transformation. GT was essential for both children to survive and to clear therapy-refractory infections, and future GT with safer lentiviral self-inactivated (SIN) vectors may offer a therapeutic alternative for X-CGD patients suffering from life-threatening infections and lacking HLA-identical HSC donors.
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PMID:Successful Combination of Sequential Gene Therapy and Rescue Allo-HSCT in Two Children with X-CGD - Importance of Timing. 2598 36

The clinical impact of ecotropic viral integration site 1 (EVI1) expression status in myelodysplastic syndromes (MDS) is poorly defined. Here, we investigate the expression of EVI1 and its associated clinical and cytogenetic characteristics in 398 MDS patients. High EVI1 levels (EVI1high) were found more frequently in Higher-risk MDS patients. Other cytogenetic abnormalities over-represented among EVI1high cases included complex karyotype, del(5q), monosomy 7, and 12q-compared with EVI1low MDS. No specific gene mutation was found different between EVI1high and EVI1low patients, except for a high proportion of TP53 mutation in the EVI1high group. For EVIhigh patients, mean number of gene mutations was higher than that in EVI1low patients. No definite correlation was found between EVI1 expression and MDS prognosis. However, for Higher-risk MDS patients, EVI1high patients have poorer survival rate compared with EVI1low patients. Moreover, EVI1high was an adverse prognostic marker for MDS with excess blasts subtype. The addition of EVI1 could deteriorate the survival of MDS patients with chromosome 3 abnormalities, del(5q-) or monosomy 7. Taken together, EVI1 overexpression is a poor prognostic marker for higher-risk MDS group and could be included in risk stratification for MDS patients.
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PMID:EVI1 expression predicts outcome in higher-risk myelodysplastic syndrome patients. 2971 36