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)

EVI1, located at chromosome band 3q26, encodes a 1051 amino acid zinc finger protein inappropriately expressed in the leukemic cells of 2-5% of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. The activation of EVI1 often follows a chromosomal rearrangement involving band 3q26, and the two most frequent rearrangements are the t(3;3)(q21;q26) and the inv(3)(q21q26). EVI1 exists also as a longer protein that includes 188 additional amino acids at the N-terminus, named MDS1/EVI1. Both genes are expressed at very low levels in the normal bone marrow. The genomic region between the first coding exon of MDS1/EVI1 and the first coding exon of EVI1 is 150-300 kb. The majority of the chromosomal breakpoints at the 5' end of EVI1 in the t(3;3) resulting in EVI1 activation have been mapped in this region. As a consequence of the t(3;3), the cell would be unable to express MDS1/EVI1, although it would express EVI1. We have compared the transcriptional activity of MDS1/EVI1 and EVI1, and we show that MDS1/EVI1 is a strong activator of promoters containing the AGATA motif, whereas EVI1 is a repressor. In addition, whereas EVI1 represses activation by the GATA-1 erythroid factor, MDS1/EVI1 does not, and is itself repressed by EVI1. By gene fusion to the DNA-binding domain of Gal4, we further show that the activation properties of MDS1/EVI1 are restricted to an acidic segment encoded by the second and third exons in the 5' untranslated region of EVI1. We have also examined the relative expression of the two genes in normal bone marrow and in the bone marrow of leukemia patients with 3q26 rearrangements. Our results indicate that the rearrangements at 3q26 affect expression of EVI1, but not of MDS1/EVI1. We propose that rearrangements at 3q26 involving EVI1 could result in leukemia by a two-step process involving first transcriptional disruption of MDS1/EVI1, and next by inappropriately activating expression of EVI1.
 ...
PMID:The leukemia-associated gene MDS1/EVI1 is a new type of GATA-binding transactivator. 906 73

The reciprocal translocation t(1;3)(p36;q21) occurs in a subset of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), which is frequently characterized by trilineage dysplasia, in particular dysmegakaryocytopoiesis, and poor prognosis. Previously, the breakpoint cluster region (BCR) at 3q21 was identified within a 60-kilobase (kb) region centromeric to the BCR of 3q21q26 syndrome and that at 1p36.3 within a 90-kb region. In this study, genes were searched near the breakpoints at 1p36.3, and a novel gene was isolated that encoded a zinc finger protein with a PR domain, which is highly homologous to the MDS1/EVI1 gene. The novel gene, designated as MEL1 (MDS1/EVI1-like gene 1), with 1257 amino acid residues is 64% similar in nucleotide and 63% similar in amino acid sequences to MDS1/EVI1 with the same domain structure. The MEL1 gene is expressed in leukemia cells with t(1;3) but not in other cell lines or bone marrow, spleen, and fetal liver, suggesting that MEL1 is specifically in the t(1;3)(p36;q21)-positive MDS/AML. On the basis of the positional relationship between the EVI1 and MEL1 genes in each translocation, it was suggested that both genes are transcriptionally activated by the translocation of the 3q21 region with the Ribophorin I gene. Because of the transcriptional activation of the EVI1 family genes in both t(1;3)(p36;q21)-positive MDS/AML and 3q21q26 syndrome, it is suggested that they share a common molecular mechanism for the leukemogenic transformation of the cells.
 ...
PMID:A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. 1105 5

Growth factor independence 1 (GFI1) is a DNA binding zinc finger protein, which can mediate transcriptional repression mainly by recruiting histone-modifying enzymes to its target genes. GFI1 plays important roles in hematopoiesis, in particular by regulating both the function of hematopoietic stem- and precursor cells and differentiation along myeloid and lymphoid lineages. In recent years, a number of publications have provided evidence that GFI1 is involved in the pathogenesis of acute myeloid leukemia (AML), its proposed precursor, myelodysplastic syndrome (MDS), and possibly also in the progression from MDS to AML. For instance, expression levels of the GFI1 gene correlate with patient survival and treatment response in both AML and MDS and can influence disease progression and maintenance in experimental animal models. Also, a non-synonymous single nucleotide polymorphism (SNP) of GFI1, GFI1-36N, which encodes a variant GFI1 protein with a decreased efficiency to act as a transcriptional repressor, was found to be a prognostic factor for the development of AML and MDS. Both the GFI1-36N variant as well as reduced expression of the GFI1 gene lead to genome-wide epigenetic changes at sites where GFI1 occupies target gene promoters and enhancers. These epigenetic changes alter the response of leukemic cells to epigenetic drugs such as HDAC- or HAT inhibitors, indicating that GFI1 expression levels and genetic variants of GFI1 are of clinical relevance. Based on these and other findings, specific therapeutic approaches have been proposed to treat AML by targeting some of the epigenetic changes that occur as a consequence of GFI1 expression. Here, we will review the well-known role of Gfi1 as a transcription factor and describe the more recently discovered functions of GFI1 that are independent of DNA binding and how these might affect disease progression and the choice of epigenetic drugs for therapeutic regimens of AML and MDS.
 ...
PMID:Role of GFI1 in Epigenetic Regulation of MDS and AML Pathogenesis: Mechanisms and Therapeutic Implications. 3150 75