Integrated Genomics Profile of Relapsed Childhood Acute Lymphoblastic Leukemia

复发性儿童急性淋巴细胞白血病的综合基因组学特征

• 批准号: 8079476
• 负责人: William L. Carroll
• 金额: $ 17.83万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079476
• 关键词: Acute Lymphocytic Leukemia; Biological; Biological Assay; Bone Marrow; Cessation of life; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Children' s Oncology Group; DNA; Data; Diagnosis; Disease; Disease Pathway; Disease Resistance; Drug resistance; Enrollment; Epigenetic Process; Event; Extramedullary; Future; Gene Dosage; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genomics; Goals; Hand; Immunophenotyping; Inferior; Knowledge; Lead; Lesion; Malignant Neoplasms; Mediating; Molecular Genetics; Molecular Profiling; Mutation; Newly Diagnosed; Newly Diagnosed Disease; Non-accidental; Outcome; Pathway interactions; Patients; Point Mutation; Prognostic Factor; Protocols documentation; RNA Splicing; Recurrence; Recurrent disease; Relapse; Retrieval; Salvage Therapy; Sampling; Site; Stem cell transplant; Techniques; Therapeutic; Time; Transcript; Treatment Failure; Variant; cDNA Library; chemotherapy; cohort; disorder later incidence prevention; experience; genetic evolution; improved; novel; novel therapeutic intervention; outcome forecast; pre-clinical; public health relevance; success

DESCRIPTION (provided by applicant): In spite of dramatic improvements in cure rate for the most common childhood malignancy, acute lymphoblastic leukemia (ALL), one in four to five children will suffer disease reoccurrence and their prognosis is dismal. In fact relapsed ALL is the most common cause of non-accidental death in childhood. Attempts to improve relapse outcome by intensifying chemotherapy including the use of stem cell transplantation have failed to cure the majority of children. While many prognostic factors can be used to stratify therapy, only immunophenotype (T-ALL inferior prognosis), site of relapse (bone marrow inferior to isolated extramedullary) and timing of relapse (early relapse defined as < 36 months from initial diagnosis inferior compared to late relapse) are predictive of salvage. To discover the underlying pathways that mediate drug resistance in childhood ALL we have used high throughput genomic techniques to analyze differences in global gene expression and copy number abnormalities (CNAs) in matched diagnosis/relapse paired samples from children enrolled on Children's Oncology Group (COG) protocols. Our early results indicate that most cases of early relapse are characterized by a proliferative gene signature and we suggest that these clones exist at diagnosis. In contrast, we hypothesize that many cases of late relapse occur through acquisition of additional genetic and/or epigenetic changes. Importantly, we have identified attractive targets for novel therapeutic approaches including a subset that have been validated in preclinical assays. The goals of this application are to extend these observations and confirm our hypothesis through the following specific aims: 1) discover biological pathways responsible for the emergence of resistant disease by identifying novel somatic point mutations and fusion transcripts through direct transcriptome sequencing in four diagnosis/relapse pairs 2) to determine if the somatic lesions identified in aim 1 represent recurring genetic lesions associated with relapse, we will screen a large cohort of additional diagnosis/relapse pairs using a combination of direct sequencing and Taqman assays of complementary and genomic DNA 3) to prioritize those mutations that are most likely to be associated with drug resistance, we will develop an integrated genomic analysis of relapsed ALL where we will integrate the mutational analyses developed in aims 1 and 2 with our previous results from gene expression and copy number analysis. The results of these studies will lead to an understanding of the cellular origin of relapsed disease and the pathways that are responsible for treatment failure. Such information will lead to the discovery of pathways that can be targeted in future trials. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Although the majority of children who are newly diagnosed with acute lymphoblastic leukemia (ALL) are now cured, recurrences develop in 25% of cases. Most of these recurrences develop unpredictably and our success in treating relapse has significantly lagged behind that of newly diagnosed disease. In fact, only approximately one third of children with recurrent ALL survive long-term. The goal of this project is to develop a better understanding of the molecular genetic events that lead to relapse so that this knowledge can be used to identify more effective preventative and therapeutic strategies.

描述（由申请人提供）：尽管最常见的儿童恶性肿瘤急性淋巴细胞白血病（ALL）的治愈率有了显著提高，但四分之一到五分之一的儿童将遭受疾病复发，其预后令人沮丧。事实上，复发性ALL是儿童非意外死亡的最常见原因。通过加强化疗（包括使用干细胞移植）来改善复发结果的尝试未能治愈大多数儿童。虽然许多预后因素可用于分层治疗，但只有免疫表型（T-ALL预后较差）、复发部位（骨髓低于孤立的髓外）和复发时间（早期复发定义为与晚期复发相比，初始诊断< 36个月）可预测挽救。为了发现介导儿童ALL耐药性的潜在途径，我们使用高通量基因组技术分析了来自儿童肿瘤学组（COG）方案的儿童的匹配诊断/复发配对样本中的全局基因表达和拷贝数异常（CNA）的差异。我们的早期研究结果表明，大多数早期复发病例的特征是增殖性基因签名，我们认为这些克隆存在于诊断。相反，我们假设许多晚期复发病例是通过获得额外的遗传和/或表观遗传变化而发生的。重要的是，我们已经确定了新的治疗方法，包括已在临床前试验中验证的子集有吸引力的目标。本申请的目标是扩展这些观察结果，并通过以下具体目标证实我们的假设：1）通过在四个诊断/复发对中通过直接转录组测序鉴定新的体细胞点突变和融合转录物，发现负责抗性疾病出现的生物学途径为了确定AIM 1中鉴定的体细胞损伤是否代表与复发相关的复发性遗传损伤，我们将使用互补和基因组DNA的直接测序和Taqman测定的组合筛选大量额外的诊断/复发对3）以优先考虑那些最可能与耐药性相关的突变，我们将开发复发ALL的综合基因组分析，其中我们将整合目标1和2中开发的突变分析与我们先前的基因表达和拷贝数分析结果。这些研究的结果将导致对复发性疾病的细胞起源以及导致治疗失败的途径的理解。这些信息将导致发现可以在未来试验中靶向的途径。 公共卫生关系： 虽然大多数新诊断为急性淋巴细胞白血病（ALL）的儿童现在已经治愈，但25%的病例会复发。大多数复发性疾病的发展是不可预测的，我们在治疗复发方面的成功明显落后于新诊断疾病。事实上，只有大约三分之一的复发性ALL儿童能够长期存活。该项目的目标是更好地了解导致复发的分子遗传事件，以便这些知识可用于确定更有效的预防和治疗策略。