Department of Medicine, Queen Mary Hospital, University of Hong King, Pokfulam, Hong Kong.
Blood. 2011 Nov 24;118(22):5901-4. doi: 10.1182/blood-2011-06-361022. Epub 2011 Oct 5.
We postulated that MIR34B/C, a direct transcriptional target of TP53, might be inactivated by promoter hypermethylation in multiple myeloma (MM). MIR34B/C promoter methylation was studied in 8 normal marrow controls, 8 MM cell lines, 95 diagnostic, and 23 relapsed/progressed MM samples by methylation-specific PCR. MIR34B/C was methylated in 6 (75.0%) MM cell lines but not normal controls. 5-Aza-2'-deoxycytidine led to MIR34B/C promoter demethylation and MIR34B reexpression. Moreover, restoration of MIR34B led to reduced cellular proliferation and enhanced apoptosis of myeloma cells. In primary samples, methylation of MIR34B/C occurred in 5.3% at diagnosis and 52.2% at relapse/disease progression (P < .001). In 12 MM patients with paired samples at diagnosis and relapse/progression, MIR34B/C methylation was acquired in 6 at relapse/progression. In conclusion, MIR34B/C is a tumor suppressor in myeloma. Hypermethylation of MIR34B/C is tumor-specific. Frequent MIR34B/C hypermethylation during relapse/progression but not at diagnosis implicated a role of MIR34B/C hypermethylation in myeloma relapse/progression.
我们假设 MIR34B/C，一种 TP53 的直接转录靶标，可能在多发性骨髓瘤 (MM) 中由于启动子超甲基化而失活。通过甲基化特异性 PCR 研究了 8 个正常骨髓对照、8 个 MM 细胞系、95 个诊断和 23 个复发/进展 MM 样本中的 MIR34B/C 启动子甲基化。6 个 (75.0%) MM 细胞系发生 MIR34B/C 甲基化，但正常对照无。5-Aza-2'-脱氧胞苷导致 MIR34B/C 启动子去甲基化和 MIR34B 重新表达。此外，恢复 MIR34B 导致骨髓瘤细胞的增殖减少和凋亡增强。在原发性样本中，MIR34B/C 的甲基化在诊断时为 5.3%，在复发/进展时为 52.2% (P <.001)。在 12 例具有诊断和复发/进展时配对样本的 MM 患者中，6 例在复发/进展时获得 MIR34B/C 甲基化。总之，MIR34B/C 是骨髓瘤中的一种肿瘤抑制因子。MIR34B/C 的高甲基化是肿瘤特异性的。在复发/进展期间频繁发生 MIR34B/C 高甲基化而不是在诊断时，提示 MIR34B/C 高甲基化在骨髓瘤复发/进展中起作用。
