Residual DNA methylation at remission is prognostic in adult Philadelphia chromosome-negative acute lymphocytic leukemia.
Residual DNA methylation at remission is prognostic in adult Philadelphia chromosome-negative acute lymphocytic leukemia.
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DOI：
10.1182/blood-2008-02-141002
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发表时间：
2009-02
期刊：
影响因子：
20.3
通讯作者：
Hui Yang;T. Kadia;Lianchun Xiao;C. Bueso-Ramos;K. Hoshino;D. Thomas;S. O'brien;E. Jabbour;S. Pierce;G. Rosner;H. Kantarjian;G. Garcia-Manero
中科院分区：
文献类型：
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作者：
Hui Yang;T. Kadia;Lianchun Xiao;C. Bueso-Ramos;K. Hoshino;D. Thomas;S. O'brien;E. Jabbour;S. Pierce;G. Rosner;H. Kantarjian;G. Garcia-Manero
急性淋巴细胞白血病（ALL）治疗前异常的DNA甲基化模式在复发时是稳定的。我们假设在形态学缓解时检测到残留的甲基化改变可能预示更差的预后。我们开发了一种实时亚硫酸氢盐聚合酶链反应检测方法，并分析了199例费城染色体阴性和MLL（-）ALL患者在初始缓解时p73、p15和p57（KIP 2）的甲基化水平。18例（9.5%）患者检测到残留的p73甲基化，33例（17.4%）检测到残留的p15甲基化，7例（3.7%）检测到残留的p57（KIP 2）甲基化; 140例（74%）患者检测到0个基因甲基化，48例（25%）检测到大于或等于1个基因甲基化。在123例（65%）患者中，还研究了匹配的治疗前样本，并与缓解期样本进行了比较：在82例至少有一个基因初始异常甲基化的患者中，59例（72%）在缓解期没有检测到甲基化，23例（28%）有可检测到的残留甲基化。通过多变量分析，残留p73甲基化的存在与首次完全缓解（风险比=2.68，P= 0.003）和总生存期（风险比=2.69，P= 0.002）显著缩短相关。总之，表观遗传学改变的检测允许识别具有标准风险但预后不良的ALL患者。
Pretreatment aberrant DNA methylation patterns are stable at time of relapse in acute lymphocytic leukemia (ALL). We hypothesized that the detection of residual methylation alterations at the time of morphologic remission may predict for worse prognosis. We developed a real-time bisulfite polymerase chain reaction assay and analyzed the methylation levels of p73, p15, and p57(KIP2) at the time of initial remission in 199 patients with Philadelphia chromosome-negative and MLL(-) ALL. Residual p73 methylation was detected in 18 (9.5%) patients, p15 in 33 (17.4%), and p57(KIP2) in 7 (3.7%); 140 (74%) patients had methylation of 0 genes and 48 (25%) of more than or equal to 1 gene. In 123 (65%) patients, matched pretreatment samples were also studied and compared with remission ones: in 82 of those with initial aberrant methylation of at least one gene, 59 (72%) had no detectable methylation at remission and 23 (28%) had detectable residual methylation. By multivariate analysis, the presence of residual p73 methylation was associated with a significant shorter duration of first complete remission (hazard ratio=2.68, P= .003) and overall survival (hazard ratio=2.69, P= .002). In conclusion, detection of epigenetic alterations allows the identification of patients with ALL with standard risk but with poor prognosis.