Frequent and Simultaneous Epigenetic Inactivation of <em>TP53</em> Pathway Genes in Acute Lymphoblastic Leukemia

Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n = 48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-2′-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p = 0.001) and mortality (p<0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p = 0.006) and overall survival (OS) (p = 0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL.异常DNA甲基化是急性淋巴细胞白血病（Acute Lymphoblastic Leukemia, ALL）患者中最常见的分子改变之一。本研究采用甲基化微珠阵列，对初诊时期的48例ALL样本队列中807个与癌症相关的基因的甲基化状态进行了分析。结果显示，154个基因在超过10%的ALL样本中发生甲基化。值得注意的是，13个参与TP53通路的基因的表达因高甲基化而下调。使用5-氮杂-2′-脱氧胞苷（5-aza-2′-deoxycitidine）、姜黄素（Curcumin）或Nutlin-3直接或间接激活TP53通路，可诱导ALL细胞凋亡率升高。本研究针对初始48例患者队列得到的研究结果，在200例新诊断ALL患者的第二批队列中进行了回顾性验证。在78%的受试患者中可检测到TP53通路相关13个基因中至少1个发生甲基化，该现象与较高的复发率（p=0.001）和死亡率（p<0.001）显著相关；多因素分析结果表明，该甲基化状态是无病生存期（disease-free survival, DFS）（p=0.006）与总生存期（overall survival, OS）（p=0.005）的独立预后因素。上述所有研究结果表明，在绝大多数ALL患者中，TP53通路可通过表观遗传机制发生异常改变，且与患者预后密切相关。可逆转表观遗传异常或直接激活p53通路的化合物疗法，为ALL患者提供了全新的治疗选择。