Soderholm J, Kobayashi H, Mathieu C, Rowley J D, Nucifora G
Department of Medicine, University of Chicago, IL, USA.
Leukemia. 1997 Mar;11(3):352-8. doi: 10.1038/sj.leu.2400584.
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.
EVI1定位于染色体3q26带，编码一种含1051个氨基酸的锌指蛋白，在2% - 5%的急性髓系白血病（AML）和骨髓增生异常综合征（MDS）患者的白血病细胞中异常表达。EVI1的激活通常伴随着涉及3q26带的染色体重排，最常见的两种重排是t(3;3)(q21;q26)和inv(3)(q21q26)。EVI1也以一种更长的蛋白形式存在，该蛋白在N端包含另外188个氨基酸，名为MDS1/EVI1。这两个基因在正常骨髓中表达水平都非常低。MDS1/EVI1的第一个编码外显子和EVI1的第一个编码外显子之间的基因组区域为150 - 300 kb。在导致EVI1激活的t(3;3)中，EVI1 5'端的大多数染色体重排断点都定位在该区域。由于t(3;3)，细胞将无法表达MDS1/EVI1，尽管它会表达EVI1。我们比较了MDS1/EVI1和EVI1的转录活性，结果表明MDS1/EVI1是含AGATA基序启动子的强激活剂，而EVI1是一种抑制剂。此外，EVI1可抑制GATA - 1红系因子的激活作用，而MDS1/EVI1则不会，且MDS1/EVI1本身会被EVI1抑制。通过与Gal4的DNA结合结构域进行基因融合，我们进一步表明MDS1/EVI1的激活特性仅限于EVI1 5'非翻译区第二和第三个外显子编码的一个酸性片段。我们还检测了这两个基因在正常骨髓以及3q26重排的白血病患者骨髓中的相对表达。我们的结果表明，3q26的重排影响EVI1的表达，但不影响MDS1/EVI1的表达。我们提出，涉及EVI1的3q26重排可能通过两步过程导致白血病，第一步是MDS1/EVI1的转录中断，第二步是EVI1的表达被不适当激活。
