BIOMARKERS OF TREATMENT RELATED LEUKEMIA

治疗相关白血病的生物标志物

• 批准号: 6350439
• 负责人: Carolyn A Felix
• 金额: $ 36.94万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350439
• 关键词: DNA gyrase; alkylating agents; biomarker; chromosome translocation; clinical research; cyclophosphamide; cytochrome P450; doxorubicin; enzyme inhibitors; etoposide; genetic markers; human subject; iatrogenic disease; leukemia; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neuroblastoma; pediatric neoplasm /cancer; polymerase chain reaction; southern blotting

DESCRIPTION: (Adapted from the investigator's abstract) The objective of this work is to develop new avenues to identify undergoing anticancer therapy who are at increased risk of leukemia as a treatment complication and to facilitate detection of the leukemic clone earlier in the course of the disease. For children with metastatic neuroblastoma receiving N6 therapy, the incidence of leukemia is 7%. About 40% of cases are related to alkylating agent therapy and have chromosome 5 and/or 7 loss; about 40% have translocation of the MLL gene at chromosome band 11q23, which occurs in leukemias related to DNA topoisomerase II inhibitors. Because of its efficacy against neuroblastoma, N6 therapy will be incorporated into the high-risk neuroblastoma trial for the Children's Cancer Group. Etoposide, doxorubicin and cyclophosphamide used in N6 therapy are metabolized by cytochrome P-450 (CYP) 3A; all are associated with leukemia as a treatment complication. The metabolites have genotoxic properties that may be relevant to leukemogenesis. The promoter of the CYP3A4 gene is polymorphic. Prior studies showed that the CYP3A4 wild-type genotype increased and CYP3A4 variant genotypes decrease the risk of treatment-related leukemia with MLL gene translocations. Prior studies also showed that the MLL gene translocation can be present early in the course therapy at how cumulative doses of DNA topoisomerase II inhibitors. MLL presents an extreme example of a translocation involving many partner genes; Southern blot analysis and cDNA panhandle PCR are two methods that can track the translocations in preleukemic samples regardless of the partner gene. They hypothesize that CYP3A4 genotype and MLL gene translocations are relevant biomarkers for treatment-related leukemia. The plans of the cooperative group to use N6 therapy not only mandate systematic investigation of who is most at risk, but also provide a unique clinical opportunity to examine CYP3A4 genotype and MLL gene translocations as a relevant biomarkders in the context of the therapeutic trial. The purpose of aim 1 is to validate the association of CYP3A4 genotype with treatment-related leukemia. The purpose of aims 2 and 3 is to determine and compare the utility of MLL gene translocations, detected by Southern blot analysis and cDNA panhandle PCR, as leukemia-specific markers that predict development of disease. The purpose of aim 4 is to explore the baseline frequency of MLL gene translocations in untreated pediatric patients diagnosed with neuroblastoma and to determine how chemotherapy affects this frequency during the course of treatment. Risk factors for treatment-related leukemia are poorly understood. Predictive biomarker assays will enable rational modifications of primary cancer therapies and provide new opportunities for early intervention.

描述：（改编自研究者的摘要）此目的 工作是开发新的途径来识别正在接受抗癌治疗的人 患白血病作为治疗并发症的风险增加，并促进 在病程早期检测白血病克隆。为了 接受 N6 治疗的转移性神经母细胞瘤儿童的发生率 白血病是7%。约 40% 的病例与烷化剂治疗有关 5 号和/或 7 号染色体缺失；约 40% 存在 MLL 基因易位 位于染色体带 11q23，发生在与 DNA 相关的白血病中 拓扑异构酶 II 抑制剂。由于其对神经母细胞瘤的功效，N6 治疗将被纳入高危神经母细胞瘤试验中 儿童癌症小组。 N6中使用的依托泊苷、阿霉素和环磷酰胺 治疗通过细胞色素 P-450 (CYP) 3A 代谢；全部都与 白血病作为治疗并发症。代谢物具有遗传毒性 这可能与白血病的发生有关。 CYP3A4基因的启动子是 多态性。先前的研究表明 CYP3A4 野生型基因型增加 和 CYP3A4 变异基因型可降低治疗相关白血病的风险 MLL 基因易位。先前的研究还表明 MLL 基因 易位可以在治疗过程的早期出现，累积程度如何 DNA拓扑异构酶II抑制剂的剂量。 MLL 提供了一个极端的例子 涉及许多伙伴基因的易位； Southern印迹分析和cDNA panhandle PCR 是两种可以追踪白血病前期易位的方法 样本与伴侣基因无关。他们假设 CYP3A4 基因型 和 MLL 基因易位是治疗相关的相关生物标志物 白血病。合作组使用N6疗法的计划不仅强制 对谁面临最大风险进行系统调查，同时也提供了独特的方法 检查 CYP3A4 基因型和 MLL 基因易位的临床机会 治疗试验中的相关生物标志物。目的 目标 1 是验证 CYP3A4 基因型与治疗相关的关联 白血病。目标 2 和 3 的目的是确定和比较效用 MLL 基因易位，通过 Southern blot 分析和 cDNA 检测 panhandle PCR，作为预测白血病发展的特异性标记 疾病。目标4的目的是探索MLL基因的基线频率 未经治疗的诊断为神经母细胞瘤的儿科患者中的易位 以确定化疗过程中如何影响该频率 治疗。对治疗相关白血病的危险因素知之甚少。 预测性生物标志物测定将使初级生物标志物的合理修改成为可能 癌症治疗并为早期干预提供新的机会。