Genomische Charakterisierung der T-ALL mit Hilfe der Mikroarray-comparative genomic Hybridisierung (Array-CGH)

急性淋巴细胞白血病（ALL）是儿童中最常见的癌症，几乎占15岁以下儿童所有癌症诊断的%。由于对儿童ALL的病因和危险因素知之甚少，儿童ALL的成功治疗在很大程度上取决于对患者疾病亚型的准确评估，这是由基因重排和改变决定的。染色体分析（细胞遗传学）是白血病常规分型的一种方法。不幸的是，传统的细胞遗传学方法具有有限的分辨率，而更高分辨率的方法仅询问已知的基因组畸变。因此，据信，许多遗传缺陷的潜在ALL逃脱检测通过传统的细胞遗传学方法。在这项提案中，我们计划使用最先进的遗传技术，基于阵列的比较基因组杂交（阵列CGH）和分子细胞遗传学技术来识别儿童T细胞急性淋巴细胞白血病（T-ALL）中发生的基因组失衡，这是儿童ALL的更具侵略性的形式。阵列CGH是一种新兴的高分辨率和高通量筛查癌细胞染色体不平衡的技术。在CLL的试点研究中，我们的实验室已经证明，阵列CGH可以检测所有已知的染色体不平衡，以及确定新的，复发的和精确的信息基因组标记。类似地，我们相信阵列CGH研究将在T-ALL中产生信息性生物标志物，这将帮助我们识别具有更具侵袭性的T-ALL亚型的患者（其将是更具侵袭性和更早的治疗机构的候选人）。此外，与T-ALL相关的失调基因的鉴定可以提供对白色血细胞恶性肿瘤的分子机制的见解。拟议的研究将（1）确定和表征人类基因组中的大规模拷贝数变异，以进行准确的阵列CGH分析，（2）确定用于TALL诊断的新遗传标记，以及（3）研究治疗后和复发时T-ALL中发生的基因组变化。

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, accounting for almost % of all cancer diagnoses in children under the age of 15. Since little is known about the causes and risk factors for childhood ALL, successful treatment of pediatric ALL weighs heavily on accurate assessment of the patient s disease subtype, determined by genetic rearrangements and alterations. Chromosomal analysis (cytogenetics) is one means by which leukemias are routinely subtyped. Unfortunately, conventional cytogenetic methods have limited resolution while higher-resolution methods only interrogate known genomic aberrations. Thus, it is believed that many of the genetic defects underlying ALL escape detection via conventional cytogenetic methodologies. In this proposal, we plan on using state-of-the-art genetic technologies, array-based comparative genomic hybridization (array-CGH) and multicolor molecular cytogenetic technologies to identify genomic imbalances that occur in pediatric T-cell acute lymphoblastic leukemia (T-ALL), the more aggressive form of childhood ALL. Array-CGH is an emerging technology for high-resolution and highthroughput screening of cancer cells for chromosomal imbalances. In a pilot study on CLL, our laboratory has already demonstrated that array-CGH can detect all known chromosomal imbalances, as well as identify novel, recurrent and prognostically-informative genomic markers. Similarly, we believe that array- CGH studies will yield informative biomarkers in T-ALL that will help us to identify patients with more aggressive subtypes of T-ALL (who would be candidates for more aggressive and earlier institution of therapy). Moreover, the identification of dysregulated genes associated with T-ALL could provide insights into the molecular mechanisms of white blood cell malignancies. The proposed studies will (1) Identify and characterize large-scale copy number variations in the human genome for accurate array-CGH profiling, (2) Identify new genetic markers for TALL diagnosis, and (3) Investigate the genomic changes that occur in T-ALL after therapy and at relapse.