Detection and Therapy of Residual Leukemia in Children

描述(由申请人提供)：尽管治愈率不断提高，但大约四分之一的急性淋巴细胞白血病(ALL)儿童最终死于他们的疾病。拟议研究的长期目标是改善这些患者的临床结果。在缓解诱导后及早发现残留疾病可能会确定哪些患者将从强化治疗中受益，这将提高长期幸存者的比例。在上一次资助期间，开发了检测儿童微小(即亚微观)残留病(MRD)的敏感免疫学方法，一项临床研究表明，用这些方法检测的MRD是一个强大的、独立的预后指标。 在儿童ALL的治疗方案中常规纳入MRD检测的主要剩余障碍是缺乏可成功应用于所有患者的实用方法。在特定目标1中提出的研究的目的是确定简单的抗体板，允许实用、可靠和通用的流式细胞仪监测ALL儿童的MRD。基因芯片分析的初步结果将与通过比较正常CD19+CD10+细胞和284例新诊断的B系ALL患者的基因图谱而获得的信息相结合。流式细胞仪的研究将集中在选定的蛋白质，因为它们在B系ALL细胞中过度表达，并预测它们在细胞表面的定位。在特定目标2中提出的研究试图确定外周血中可检测到的MRD是否与更具侵袭性的B系相关，所有这些都是初步结果所表明的。这一目标下的研究还将评估B系ALL细胞过早退出骨髓微环境的倾向是否与黏附分子、趋化因子受体或基质降解金属蛋白酶的表达特征模式有关。根据初步结果，特定目标3的研究将确定外周血MRD水平是否反映了T系ALL临床缓解儿童骨髓中的MRD水平。这一努力的成功可以通过克服连续的骨髓愿望带来的实际和伦理限制，从根本上改善这些患者的缓解研究。

DESCRIPTION (provided by applicant): Despite increasing cure rates, approximately one fourth of children with acute lymphoblastic leukemia (ALL) eventually die of their disease. The long-term objective of the proposed research is to improve the clinical outcomes of these patients. Early detection of residual disease after remission induction may identify patients who will benefit from intensified treatment, which should then boost the proportion of long-term survivors. During the previous funding period, sensitive immunologic methods of detecting minimal (i.e., submicroscopic) residual disease (MRD) in childhood ALL were developed, and a clinical study demonstrated that MRD detected by these methods is a powerful, independent prognostic indicator. The main remaining obstacle to the routine incorporation of MRD assays in treatment protocols for childhood ALL is the lack of practical methods that can be successfully applied to all patients. The objective of the studies proposed in Specific Aim 1 is to identify simple antibody panels that allow practical, reliable, and universal flow cytometric monitoring of MRD in children with ALL. Initial findings of cDNA array analyses will be integrated with information derived from comparing the gene profile of normal CD19+CD10+ cells to that of 284 newly diagnosed cases of B-lineage ALL. Flow cytometric studies will focus on proteins selected because of their overexpression in B-lineage ALL cells and their predicted localization on the cell surface. Studies proposed in Specific Aim 2 seek to determine whether detectable MRD in peripheral blood is associated with a more aggressive form of B-lineage ALL as suggested by preliminary results. Studies under this aim will also assess whether the propensity of B-lineage ALL cells to prematurely exit the bone marrow microenvironment is associated with characteristic patterns of expression of adhesion molecules, chemokine receptors or matrix-degrading metalloproteinases. Studies in Specific Aim 3 will determine whether peripheral-blood MRD levels reflect those in the bone marrow in children with T-lineage ALL in clinical remission, as suggested by preliminary results. Success in this endeavor could radically improve remission studies in these patients by overcoming the practical and ethical constraints posed by sequential bone marrow aspirations