Disease relevance of EVI1

• The EVI1 gene, located at chromosome band 3q26, is overexpressed in some myeloid leukemia patients with breakpoints either 5' of the gene in the t(3;3)(q21;q26) or 3' of the gene in the inv(3)(q21q26) [1].
• Two genes have been implicated in leukemias of patients with abnormalities of chromosome 3, band q26: EVI1, which can be activated over long distances by chromosomal rearrangements involving 3q26, and EAP, a ribosomal gene that fuses with AML1 in a therapy-related myelodysplasia patient with a t(3;21)(q26.2;q22) [2].
• Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders [3].
• Pronounced differences in the expression of the 5'-end variants were noted in response to all-trans retinoic acid: in a human teratocarcinoma cell line, only the EVI1 transcript variants containing alternative exons 1a and 1b were upregulated in response to this agent [4].
• It should, therefore, be useful both for studying the biological characteristics of acute myelogenous leukemia M0 subtype and for investigating the role of the EVI1 gene in leukemogenesis [5].

High impact information on EVI1

• Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia [6].
• Screening of a cDNA library of the t(3;21)-carrying leukemic cell line cells (SKH1) resulted in the isolation of two potentially complete AML1-EVI-1 chimeric cDNAs of 6 kb [6].
• One result of this translocation is a fusion between the AML1, MDS1, and EVI1 genes, which encodes a transcription factor of approximately 200 kDa [7].
• This murine model for AME-induced AML will help dissect the molecular mechanism of AML and the molecular biology of the AML1, MDS1, and EVI1 genes [7].
• Intergenic splicing of MDS1 and EVI1 occurs in normal tissues as well as in myeloid leukemia and produces a new member of the PR domain family [1].

Chemical compound and disease context of EVI1

• Arsenic trioxide and thalidomide combination produces multi-lineage hematological responses in myelodysplastic syndromes patients, particularly in those with high pre-therapy EVI1 expression [8].

Biological context of EVI1

• These results are important in view of the fact that EVI1 and MDS1 are involved in leukemia associated with chromosomal translocation breakpoints in the region between these genes [1].
• In this report, we present evidence indicating that MDS1 exists in normal tissues both as a unique transcript and as a normal fusion transcript with EVI1, with an additional 188 codons at the 5' end of the previously reported EVI1 open reading frame [1].
• The proto-oncogene EVI1 encodes a DNA binding protein and is located on chromosome 3q26 [9].
• Furthermore, a comparison can be made with the formation of an AML1/MDS1/EVI1 fusion gene in translocations (3;21)(q26;q22) [3].
• The resulting chimeric transcript consists of the first two exons of ETV6 fused to MDS1 sequences, which in turn is fused to the second exon of the EVI1 gene [3].

Anatomical context of EVI1

• Retroviral insertional activation of the EVI1 oncogene does not prevent G-CSF-induced maturation of the murine pluripotent myeloid cell line 32Dcl3 [10].
• RT-PCR analysis of various types of hematopoietic cells revealed that the EVI1 gene is expressed specifically in CD34(+) cells, megakaryocytes, and platelets [11].
• Three cases of myeloid/NK cell precursor BC in CML have been reported, but this case is the first to present with Ph and EVI1 abnormality [12].
• AML1/EVI1/+ embryo showed defective hematopoiesis in the fetal liver and died around embryonic day 13.5 (E13.5) as a result of hemorrhage in the central nervous system [13].
• Blastic cells from the patient strongly expressed the EVI1 gene, which is located on 3q26 and is normally suppressed in bone marrow cells [14].

Associations of EVI1 with chemical compounds

• Targeted Degradation of the AML1/MDS1/EVI1 Oncoprotein by Arsenic Trioxide [15].
• Both low/high risk MDS may benefit significantly from therapy with ATO/thalidomide, and those with high pre-therapy EVI1 expression may be uniquely sensitive [8].

Regulatory relationships of EVI1

• Finally, we show that EVI1 up-regulates cell proliferation in BRG1-positive 32Dcl3 cells but not in BRG1-negative SW13 cells [16].

Other interactions of EVI1

• The region of recurrent increase is approximately 30 Mb in extent, ranging from EVI1 to TFRC [17].
• Taken together, these data support the hypothesis that the interaction with BRG1 is important for up-regulation of cell-growth by EVI1 [16].
• When UT-7/GM cells were cultured with TPO, the level of EVI1 expression was increased, along with increased numbers of polynuclear megakaryocytes and expression of the platelet factor 4 (PF-4) gene [11].
• Together, these data indicate that EVI1 activation is likely due not to the generation of a novel fusion gene with CDK6 but to a position effect dysregulating its transcriptional pattern [18].
• The clustering was driven by the presence of chromosomal lesions (e.g., t(8;21), t(15;17), and inv(16)), particular genetic mutations (CEBPA), and abnormal oncogene expression (EVI1) [19].

Analytical, diagnostic and therapeutic context of EVI1

• Confocal microscopy analysis shows that in the majority of the cells, EVI1 is nuclear and diffused, whereas in about 10% of the cells EVI1 localizes in nuclear speckles [20].
• No structural alterations of the EVI1 and TEL genes were detected by Southern blot and PCR analyses [14].
• We have studied six individuals with AML and inv(3)(q21q26) for disruptions to the EVI1 locus by in situ hybridization and long-range mapping [21].
• To assess whether native EVI1 binds to these sites in EVI1-transformed myeloid cells, we performed chromatin immunoprecipitation in 32Dcl3 and NFS58 cells, using anti-EVI1 antisera, and we showed that the majority of these sites is bound by wild type EVI1 [22].
• Therefore, we further characterized the chromosomal breakpoint by pulsed-field gel electrophoresis near EVI1 [23].

References