BIOMARKERS OF TREATMENT RELATED LEUKEMIA

治疗相关白血病的生物标志物

• 批准号: 6701287
• 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 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6701287
• 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：（改编自研究者摘要）本研究的目的 我们的工作是开发新的途径来识别正在接受抗癌治疗的人， 作为一种治疗并发症， 在疾病过程的早期检测白血病克隆。为 接受N6治疗的转移性神经母细胞瘤儿童， 白血病占7%。约40%的病例与烷化剂治疗有关， 有5号和/或7号染色体丢失;约40%有MLL基因易位 位于染色体带11 q23，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疗效，N6 治疗将被纳入高风险神经母细胞瘤试验， 儿童癌症小组。依托泊苷、阿霉素和环磷酰胺用于N6 治疗通过细胞色素P-450（CYP 3A）3A代谢;所有这些都与 白血病作为治疗并发症。代谢产物具有遗传毒性 可能与白血病发生有关CYP 3A 4基因的启动子是 多态的先前的研究表明，CYP 3A 4野生型基因型增加 和CYP 3A 4变异基因型降低治疗相关白血病的风险 MLL基因易位先前的研究也表明，MLL基因 易位可以出现在治疗过程的早期， 剂量的DNA拓扑异构酶II抑制剂。MLL提出了一个极端的例子， 涉及多个伴侣基因的易位; Southern印迹分析和cDNA 柄状PCR是两种可以追踪白血病前期易位的方法， 无论伴侣基因如何。他们假设CYP 3A 4基因型 和MLL基因易位是治疗相关的 白血病合作小组使用N6疗法的计划不仅要求 系统调查谁是最危险的，而且还提供了一个独特的 检查CYP 3A 4基因型和MLL基因易位的临床机会， 在治疗试验的背景下，的目的 目的1是验证CYP 3A 4基因型与治疗相关的 白血病目标2和目标3的目的是确定和比较 MLL基因易位，通过Southern印迹分析和cDNA检测 Panhandle PCR作为白血病特异性标记物，可预测 疾病目的4：探讨MLL基因的基线频率 在未经治疗的诊断为神经母细胞瘤的儿科患者中的易位， 以确定化疗如何影响这一频率在过程中， 治疗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能够合理地修改主要生物标志物。 癌症治疗，并为早期干预提供新的机会。