Cigdem Sadik, Saito Shoko, Nishikata Daiki, Nagata Kyosuke, Okuwaki Mitsuru
Laboratory of Biochemistry, School of Pharmacy, Kitasato University, Minato-ku, Japan.
Department of Infection Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Genes Cells. 2021 Oct;26(10):830-837. doi: 10.1111/gtc.12886. Epub 2021 Aug 8.
SET-Nup214 is a recurrent fusion gene that is mainly observed in T-cell acute lymphoblastic leukemia (T-ALL). Dysregulation of homeobox (Hox) genes is frequently observed in patients with leukemia. Consistent with this, HoxA genes are upregulated in the SET-Nup214 T-ALL cell line and patients. Although SET-Nup214 has been reported to be recruited to the promoter regions of HoxA genes, the detailed mechanisms of how SET-Nup214 specifically binds to HoxA gene promoters and regulates HoxA gene expression are not known. In this study, we demonstrated that SET-Nup214 interacts with MLL via the SET acidic region of SET-Nup214. SET-Nup214 and MLL cooperatively enhance the promoter activity of the HoxA10 gene. Neither the SET region alone nor the Nup214 region alone sufficiently enhanced the HoxA10 gene promoter. Our results indicated that the SET portion of the SET-Nup214-fusion protein is important for interactions with MLL and transcription enhancement of the HoxA10 gene. Thus, our study will contribute to the understanding of how SET-Nup214 and MLL disturb the expression of HoxA10 gene in leukemia.
SET-Nup214是一种常见的融合基因，主要在T细胞急性淋巴细胞白血病（T-ALL）中观察到。白血病患者中经常观察到同源盒（Hox）基因的失调。与此一致的是，HoxA基因在SET-Nup214 T-ALL细胞系和患者中上调。尽管已报道SET-Nup214被招募到HoxA基因的启动子区域，但SET-Nup214如何特异性结合HoxA基因启动子并调节HoxA基因表达的详细机制尚不清楚。在本研究中，我们证明SET-Nup214通过SET-Nup214的SET酸性区域与MLL相互作用。SET-Nup214和MLL协同增强HoxA10基因的启动子活性。单独的SET区域或单独的Nup214区域都不足以增强HoxA10基因启动子。我们的结果表明，SET-Nup214融合蛋白的SET部分对于与MLL的相互作用和HoxA10基因的转录增强很重要。因此，我们的研究将有助于理解SET-Nup214和MLL如何干扰白血病中HoxA10基因的表达。
