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首页> 外文期刊>Biochimica et Biophysica Acta. Gene Regulatory Mechanisms >The MDS and EVI1 complex locus (MECOM) isoforms regulate their own transcription and have different roles in the transformation of hematopoietic stem and progenitor cells
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The MDS and EVI1 complex locus (MECOM) isoforms regulate their own transcription and have different roles in the transformation of hematopoietic stem and progenitor cells

机译：MDS和EVI1复合基因座（MECOM）同种型调节其自身的转录，在造血干细胞和祖细胞的转化中具有不同的作用

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Transcriptional activation of the EVI1 oncogene (3q26) leads to aggressive forms of human acute myeloid leukemia (AML). However, the mechanism of EVI1-mediated leukemogenesis has not been fully elucidated. Previously, by characterizing the EVI1 promoter, we have shown that RUNX1 and ELK1 directly regulate EVI1 transcription. Intriguingly, bioinformatic analysis of the EVI1 promoter region identified the presence of several EVI1 potential binding sites. Thus, we hypothesized that EVI1 could bind to these sites regulating its own transcription. In this study, we show that there is a functional interaction between EVI1 and its promoter, and that the different EVI1 isoforms (EVI1-145 kDa, EVI1-Delta 324 and MDS1-EVI1) regulate the transcription of EVI1 transcripts through distinct promoter regions. Moreover, we determine that the EVI1-145 kDa isoform activates EVI1 transcription, whereas EVI1-Delta 324 and MDS1-EVI1 act as repressors. Finally, we demonstrate that these EVI1 isoforms are involved in cell transformation; functional experiments show that EVI1-145 kDa prolongs the maintenance of hematopoietic stem and progenitor cells; conversely, MDS1-EVI1 repressed hematopoietic stem and progenitor colony replating capacity. We demonstrate for the first time that EVI1 acts as a regulator of its own expression, highlighting the complex regulation of EVI1, and open new directions to better understand the mechanisms of EVI1 overexpressing leukemias.
机译：EVI1癌基因（3Q26）的转录激活导致人急性髓细胞白血病（AML）的侵略性形式。然而，EVI1介导的白血病机制尚未完全阐明。以前，通过表征EVI1启动子，我们已经表明RunX1和ELK1直接调节EVI1转录。有趣的是，EVI1启动子区域的生物信息分析鉴定出几种EVI1潜在结合位点的存在。因此，我们假设EVI1可以与这些部位结合调节其自身的转录。在这项研究中，我们表明EVI1及其启动子之间存在功能性相互作用，并且不同的EVI1同种型（EVI1-145 KDA，EVI1-DELTA 324和MDS1-EVI1）通过不同的启动子区域调节EVI1转录物的转录。此外，我们确定EVI1-145 KDA同种型激活EVI1转录，而EVI1-Delta 324和MDS1-EVI1充当阻遏物。最后，我们证明这些EVI1同种型参与了细胞转化;功能实验表明，EVI1-145 KDA延长了造血干和祖细胞的维持;相反，MDS1-EVI1压抑的造血干和祖子殖民地复制容量。我们首次证明了EVI1作为其自身表达的监管机构，突出了EVI1的复杂调节，并开放新方向以更好地理解EVI1过表达白血病的机制。

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