Koh Youngil, Kim Dae-Young, Park Sung-Hyo, Byun Hyang-Min, Kim Inho, Yoon Sung-Soo, Kim Byoung Kook, Park Eunkyung, Yang Allen S, Park Seonyang
Department of Internal Medicine, Seoul National University Hospital, Seoul National University, Seoul, Korea.
Oncol Lett. 2011 Jan;2(1):181-187. doi: 10.3892/ol.2010.208. Epub 2010 Nov 23.
To define the correlation between BCR promoter DNA methylation and response to imatinib in chronic myeloid leukemia (CML), we investigated BCR promoter DNA methylation in three groups of subjects. The first group included chronic phase patients enrolled in an imatinib dose escalation trial. In the trial, patients who failed to achieve optimal response with 400 mg/day (suboptimal responders) received an escalated imatinib dose. The level of BCR promoter DNA methylation was quantitated at baseline six months after dose escalation. The second group included patients who achieved complete cytogenetic remission after receiving 400 mg/day of imatinib (optimal responders), and the third group were the healthy controls. In the suboptimal responders, an increased BCR promoter DNA methylation at six months compared with the baseline was related to a rapid reduction in the BCR-ABL/ABL transcript level following dose escalation (p=0.001) and a longer time to treatment failure (TTFx) of the dose-escalated imatinib (p=0.008). When multivariate analysis was performed with regard to the baseline BCR-ABL transcript level, baseline BCR promoter DNA methylation, and a change in the BCR promoter DNA methylation following dose escalation, the increase in the BCR promoter DNA methylation following dose escalation was an independent predictive factor for TTFx of dose-escalated imatinib (hazard ratio, 0.294; p=0.015). The baseline BCR promoter DNA methylation level in the suboptimal responders was lower than that in BCR promoter DNA methylation in the optimal responders (p=0.001) and healthy controls (p<0.001). In both the optimal and suboptimal responders, BCR promoter DNA methylation had an inverse correlation with the duration of the 400 mg/day imatinib use. In conclusion, increased BCR promoter DNA methylation strongly correlates with a more favorable imatinib response in CML patients.
为了确定慢性髓性白血病（CML）中BCR启动子DNA甲基化与对伊马替尼反应之间的相关性，我们调查了三组受试者的BCR启动子DNA甲基化情况。第一组包括参加伊马替尼剂量递增试验的慢性期患者。在该试验中，未用400 mg/天达到最佳反应的患者（次优反应者）接受递增剂量的伊马替尼。在剂量递增后6个月的基线时对BCR启动子DNA甲基化水平进行定量。第二组包括接受400 mg/天伊马替尼后实现完全细胞遗传学缓解的患者（最佳反应者），第三组为健康对照。在次优反应者中，与基线相比，6个月时BCR启动子DNA甲基化增加与剂量递增后BCR-ABL/ABL转录水平的快速降低相关（p = 0.001）以及递增剂量伊马替尼的治疗失败时间（TTFx）延长相关（p = 0.008）。当对基线BCR-ABL转录水平、基线BCR启动子DNA甲基化以及剂量递增后BCR启动子DNA甲基化的变化进行多变量分析时，剂量递增后BCR启动子DNA甲基化的增加是递增剂量伊马替尼TTFx的独立预测因素（风险比，0.294；p = 0.015）。次优反应者的基线BCR启动子DNA甲基化水平低于最佳反应者（p = 0.001）和健康对照（p < 0.001）中的BCR启动子DNA甲基化水平。在最佳和次优反应者中，BCR启动子DNA甲基化与400 mg/天伊马替尼使用的持续时间呈负相关。总之，BCR启动子DNA甲基化增加与CML患者更有利的伊马替尼反应密切相关。
