FUSION GENES IN LEUKEMIA--DETERMINING SIGNIFICANCE

随着分子生物学的最新进展，现在有可能确定导致恶性肿瘤的遗传事件。特别地，已经鉴定了导致新的致白血病融合蛋白表达的染色体易位，并且已经从白血病患者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以用作恶性肿瘤的标志物，其允许临床研究者监测患者对治疗的反应。因此，这些基因重排可能因此被用于识别和跟踪可以从特定治疗中受益的患者群体。 该项目将利用儿童急性淋巴细胞白血病中两种最常见的基因重排，为探索分子遗传学与临床研究的整合创造一个范例。 本提案的第一个具体目的是前瞻性地确定TEL/AML 1在接受DFCI-ALL联盟方案治疗的患者中的预后意义。 TEL/AML 1是已知在任何儿科恶性肿瘤中发生的最常见的融合基因。 虽然最初报道的预后良好，但最近来自欧洲的分析表明，TEL/AML 1融合在复发时的发生频率与初始诊断时的发生频率相同。因此，有争议的预后意义的TEL/AML 1基因重排。该建议的第二个具体目的是使用定量RT-PCR技术对系列样本进行检测，以确定TEL/AML 1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E2 A/PBX 1基因重排相关的儿童白血病。第二个和第三个具体目标是基于在其他白血病的分析中开发的前提，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。 这是一个理想的时间来开发简单而有效的定量方法来检测微小残留疾病;我们可以利用越来越多的分子遗传学发现，从而最大限度地治疗儿童急性淋巴细胞白血病。

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.