Cell Cycle Controlling Genes in Adult Acute Lymphoma

描述（由申请人提供）：成人急性淋巴细胞白血病（ALL）由一组异质性淋巴细胞恶性肿瘤组成。根据费城染色体（Ph） t（9;22）的存在对治疗进行分层，这种染色体出现在15%至25%的患者中。其余患者（Ph阴性ALL）常规接受强化化疗方案，不歧视特定的分子特征。虽然初始完全缓解率超过70%，但长期生存率可能从Ph阳性患者的不到5%到Ph阴性患者的35%不等。因此，开发分子工具来识别可能受益于特定治疗干预的复发高风险患者是非常重要的。启动子相关CpG岛的异常DNA甲基化在ALL中经常观察到。在这种疾病中，直接或间接参与细胞周期控制的基因似乎是特别靶向的，在11%至34%的患者中发生p73、p15或p57KIP2的甲基化。初步数据表明，这些基因的甲基化鉴定了ALL复发的高风险群体，否则无法鉴定。在这里，我们提出了一个假设，即包括p73， p15和p57KIP2在内的途径的2个或3个基因的甲基化可以识别预后不良的ALL患者亚组。为了验证这一假设，我们提出了以下具体目标：在我们机构接受均匀治疗的300名ALL患者队列中评估p73、p15和p57KIP2的甲基化状态，并将其与生存率联系起来。样本量将提供足够的能力进行多变量分析。DNA甲基化分析将使用亚硫酸酯PCR方法进行，并将在选定的病例中使用亚硫酸酯测序进行确认。该项目的意义包括确定预后不良的患者亚组，这些患者可能受益于首次完全缓解时使用低甲基化药物和/或早期同种异体骨髓移植的靶向治疗。

DESCRIPTION (provided by applicant): Adult acute lymphocytic leukemia (ALL) consists of a heterogeneous group of lymphoid malignancies. Treatment is stratified based on the presence of the Philadelphia chromosome (Ph), t(9;22) that occurs in 15% to 25% of patients. The rest of patients (Ph negative ALL) are routinely treated with intensive chemotherapy programs that do not discriminate against specific molecular characteristics. Although initial complete remission rates are in excess of 70%, long-term survival may vary from less than 5% for Ph positive to 35% for Ph negative patients. It is therefore of great importance to develop molecular tools to identify patients at high risk for relapse that may benefit from specific therapeutic interventions. Aberrant DNA methylation of promoter associated CpG islands is frequently observed in ALL. Genes involved directly or indirectly in cell cycle control appear to be particularly targeted in this disease, with methylation of p73, p15 or p57KIP2 occurring in 11% to 34% of patients. Preliminary data suggests that methylation of these genes identifies an ALL group at high risk for relapse that cannot otherwise be identified. Here, we propose the hypothesis that methylation of 2 or 3 genes of a pathway including p73, p15 and p57KIP2 identifies a subgroup of patients with ALL with poor prognosis. To test this hypothesis, we propose the following specific aim: to evaluate the methylation status of p73, p15 and p57KIP2 in a cohort of 300 patients with ALL homogeneously treated at our institution, and correlate this with survival. The sample size will provide enough power to allow for multivariate analysis. Analysis of DNA methylation will be performed using bisulfite PCR methods, and will be confirmed using bisulfite sequencing in selected cases. The implications of this project include the identification of a subgroup of patients with poor prognosis that may benefit from targeted therapies using hypomethylating agents and/or early allogeneic bone marrow transplantation in first complete remission.