Previously we showed reduced protein and mRNA expression of the SHP1 gene in lymphoma/leukemia cell lines and patient specimens by Northern blot, RT-PCR, Western blot, and immunohistochemical analyses. In this study, aberrant methylation in the SHP1 gene promoter was detected in many B-cell leukemia/lymphoma cell lines as well as in patient specimens, including diffuse large B-cell lymphoma (methylation frequency 93%), MALT lymphoma (82%), mantle cell lymphoma (75%), plasmacytoma (100%) and follicular lymphoma (96%) by methylation-specific PCR, bisulfite sequencing, and restriction enzyme-mediated PCR analyses. The methylation frequency was significantly higher in high-grade MALT lymphoma cases (100%) than in low-grade MALT lymphoma cases (70%), which correlated well with the frequency of no expression of SHP1 protein in high-grade (80%) and low-grade MALT lymphoma (54%). It suggests that the SHP1 gene silencing with aberrant CpG methylation relates to the lymphoma progression. SHP1 protein expression was recovered in B-cell lines after the treatment of the demethylating reagent: 5-aza-2'-deoxycytidine. Transfection of the intact SHP1 gene to the hematopoietic cultured cells, which show no expression of the SHP1 gene, induced growth inhibition, indicating that gene silencing of the SHP1 gene by aberrant methylation plays an important role to get the growth advantage of the malignant lymphoma/leukemia cells. The extraordinarily high frequency (75 to 100%) of CpG methylation of the SHP1 gene in B-cell lymphoma/leukemia patient specimens indicates that the SHP1 gene silencing is one of the critical events to the onset of malignant lymphomas/leukemias as well as important implications for the diagnostic or prognostic markers and the target of gene therapy. These data support the possibility that the SHP1 gene is one of the tumor suppressor genes.

中文翻译：

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通过异常 CpG 甲基化沉默 SHP1 基因激活 B 细胞淋巴瘤/白血病的增殖。

以前我们通过 Northern 印迹、RT-PCR、蛋白质印迹和免疫组织化学分析显示淋巴瘤/白血病细胞系和患者标本中 SHP1 基因的蛋白质和 mRNA 表达减少。在这项研究中，在许多 B 细胞白血病/淋巴瘤细胞系以及患者标本中检测到 SHP1 基因启动子的异常甲基化，包括弥漫性大 B 细胞淋巴瘤（甲基化频率 93%）、MALT 淋巴瘤（82%） 、套细胞淋巴瘤 (75%)、浆细胞瘤 (100%) 和滤泡性淋巴瘤 (96%)，通过甲基化特异性 PCR、亚硫酸氢盐测序和限制酶介导的 PCR 分析。甲基化频率在高级别 MALT 淋巴瘤病例 (100%) 中显着高于低级别 MALT 淋巴瘤病例 (70%)，这与高级 (80%) 和低级 MALT 淋巴瘤 (54%) 中 SHP1 蛋白不表达的频率密切相关。这表明具有异常 CpG 甲基化的 SHP1 基因沉默与淋巴瘤进展有关。在去甲基化试剂：5-aza-2'-脱氧胞苷处理后，B 细胞系中恢复了 SHP1 蛋白表达。将完整的 SHP1 基因转染到未显示 SHP1 基因表达的造血培养细胞中，可诱导生长抑制，表明通过异常甲基化对 SHP1 基因进行基因沉默对于获得恶性淋巴瘤的生长优势具有重要作用/白血病细胞。B 细胞淋巴瘤/白血病患者标本中 SHP1 基因的 CpG 甲基化异常高频率（75% 至 100%）表明 SHP1 基因沉默是恶性淋巴瘤/白血病发作的关键事件之一，也是重要的对诊断或预后标志物和基因治疗目标的影响。这些数据支持 SHP1 基因是肿瘤抑制基因之一的可能性。