FUSION GENES IN LEUKEMIA--DETERMINING SIGNIFICANCE

随着分子生物学的最新进展，现在有可能识别导致恶性肿瘤的遗传事件。特别是，导致新型白血病融合蛋白表达的染色体易位已被鉴定，并从白血病患者中克隆了编码这些蛋白的基因。最终，这些基因重排可能成为新疗法的靶点。此外，由体细胞突变产生的融合基因可能被用作恶性肿瘤的标志，使临床研究人员能够监测患者对治疗的反应。因此，这些基因重排可能因此被用来识别和跟踪可能从特定治疗中受益的患者群体。该项目将创建一个范例，利用儿童急性淋巴细胞白血病最常见的两种基因重排，探索将分子遗传学整合到临床研究中。这项建议的第一个具体目标是前瞻性地确定TEL/AML1在接受DFCI-ALL联合方案治疗的患者中的预后意义。TEL/AML1是已知在任何儿科恶性肿瘤中出现的最常见的融合基因。虽然最初的报道提供了良好的预后，但最近来自欧洲的分析表明，TEL/AML1融合在复发时发生的频率与最初诊断时相同。因此，对于TEL/AML1基因重排的预后意义存在争议。这项建议的第二个具体目的是对序列样本使用定量RT-PCR技术来确定TEL/AML1转录本拷贝数的预后意义。第三个具体目标是将定量RT-PCR技术应用于与E2A/Pbx1基因重排相关的儿童白血病。第二个和第三个特定目标是基于在分析其他白血病时提出的前提，即融合转录本拷贝数是临床结果的预测因子。分子技术的进步预示着一个时代的到来，基因检测将成为许多疾病的常规检查。现在是开发简单有效的定量方法检测最小残留疾病的理想时机；我们可以利用分子遗传学中越来越多的发现，从而最大限度地治疗儿童急性淋巴细胞性白血病。

With recent advances in molecular biology, it is now possible to identify genetic events that lead to malignancy. In particular, chromosomal translocations that result in the expression of novel leukemogenic fusion proteins have been identified, and the genes encoding these proteins have been cloned from patients with leukemia. Ultimately, these gene rearrangements may serve as targets for novel therapies. Additionally, fusion genes arising, from somatic mutations may be used a markers of malignancy that allow clinical investigators to monitor patients' response to therapy. Thus, these gene rearrangements might therefore be used to identify and follow groups of patients who could benefit from a specific treatment. This project will create a paradigm for exploring the integration of molecular genetics into clinical investigation using the two most commonly occurring gene rearrangements in childhood acute lymphoblastic leukemia. The first specific aim of this proposal is to prospectively determine the prognostic significance of TEL/AML1 in patients treated on DFCI-ALL Consortium protocols. TEL/AML1 is the most common fusion gene known to occur in any pediatric malignancy. Though initially reported to confer a favorable prognosis, recent analyses from Europe indicate that the TEL/AML1 fusion occurs with the same frequency at relapse as it dose at initial diagnosis. There is thus controversy over the prognostic significance of the TEL/AML1 gene rearrangement. The second specific aim of this proposal is to use quantitative RT-PCR techniques on serial samples to determine the prognostic significance of TEL/AML1 transcript copy number. The third specific aim is to apply quantitative RT-PCR techniques to pediatric leukemias associated with the E2A/PBX1 gene rearrangement. The second and third specific aims are based on the premise developed in analysis of other leukemias that fusion transcript copy number is a predictor of clinical outcome. Advances in molecular technology are heralding an era when genetic testing will become routine for many diseases. It is an ideal time to develop simple and efficient quantitative approaches to minimal residual disease detection; we can capitalize on the growing number of discoveries in molecular genetics and thereby maximize the treatment of childhood acute lymphoblastic leukemia.