Department of Medical Biology and Genetics, Faculty of Medicine, TOBB University of Economics and Technology, Ankara, Turkey.
Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, Ankara, Turkey.
Biochem Genet. 2024 Apr;62(2):1263-1276. doi: 10.1007/s10528-023-10480-z. Epub 2023 Aug 16.
Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that affects the development and growth of various tissues. NF1 is a major risk factor for the development of malignancies, particularly malignant peripheral nerve sheath tumors, optic gliomas, and leukemia. NF1 encodes a neurofibromin. Three genes, EVI2A, EVI2B, and OMGP, are embedded within intron 27b of NF1. However, the function of these genes remains unclear. EVI2A and EVI2B encode for putative transmembrane proteins. Mouse homologs are associated with viral insertions involved in leukemia in mice. Mouse Evi2b has been identified as a direct target gene of C/EBPα, a transcription factor critical for myeloid differentiation. Also possible is that these genes are related to the leukemia observed in patients with NF1. These genes might act as modifiers of NF1 phenotypic variations. Therefore, we investigated the EVI2B gene in leukemia and NF1 tumors. We analyzed DNA from 10, 20, and 3 patients with NF1, leukemia, and NF1-leukemia, respectively, and six NF1 tumor tissues. DNA sequencing analysis was used to identify the viral integration sequence, and the protein amounts and EVI2B gene expression were analyzed by flow cytometry and quantitative real-time PCR techniques. The EVI2B gene expression was increased in cutaneous neurofibroma compared with the control both at the level of protein and mRNA. However, its expression in plexiform neurofibroma was decreased significantly at protein level and increased at mRNA level compare to control. Moreover, integration of 455 bases near the 3' end of the exon was detected. When this integrated sequence was blasted into the NCBI retroviral genome database, an 87% match with the HIV-1 virus envelope gene was obtained. These preliminary results show that EVI2B might be important in NF1 tumorigenesis and leukemia.
神经纤维瘤病 1 型（NF1）是一种常染色体显性疾病，影响各种组织的发育和生长。NF1 是恶性肿瘤发展的主要危险因素，特别是恶性外周神经鞘瘤、视神经胶质瘤和白血病。NF1 编码神经纤维瘤蛋白。三个基因，EVI2A、EVI2B 和 OMGP，嵌入 NF1 的内含子 27b 中。然而，这些基因的功能仍不清楚。EVI2A 和 EVI2B 编码假定的跨膜蛋白。小鼠同源物与涉及小鼠白血病的病毒插入物有关。已鉴定出小鼠 Evi2b 是转录因子 C/EBPα 的直接靶基因，C/EBPα 对于髓样分化至关重要。也有可能这些基因与 NF1 患者中观察到的白血病有关。这些基因可能作为 NF1 表型变异的修饰因子。因此，我们研究了白血病和 NF1 肿瘤中的 EVI2B 基因。我们分析了分别来自 10 名、20 名和 3 名 NF1 患者、白血病患者和 NF1-白血病患者以及 6 名 NF1 肿瘤组织的 DNA。使用 DNA 测序分析来识别病毒整合序列，并通过流式细胞术和定量实时 PCR 技术分析蛋白质含量和 EVI2B 基因表达。与对照相比，皮肤神经纤维瘤中的 EVI2B 基因表达在蛋白质和 mRNA 水平上均增加。然而，与对照相比，丛状神经纤维瘤中的蛋白质水平明显降低，mRNA 水平增加。此外，还检测到外显子 3'端附近的 455 个碱基的整合。当将此整合序列 Blast 到 NCBI 逆转录病毒基因组数据库中时，与 HIV-1 病毒包膜基因的匹配度达到 87%。这些初步结果表明，EVI2B 可能在 NF1 肿瘤发生和白血病中起重要作用。
