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　　报告题目：  Genomics of Childhood Leukaemia      

        报告人：William. L Carroll, M.D.

　　时    间：2009年6月23日（星期二）下午3：30

　　地    点：医学部会议中心205室

　　主持人：周春燕教授（北京大学基础医学院生物化学与分子生物学系教授）

　　报告人简介：

        Julie and Edward J. Minskoff Professor of Pediatrics

　　Director, NYU Cancer Institute

　　Abstract

　　The cure rate for childhood acute lymphoblastic leukemia has improved remarkably over the past four decades to over 80% today. This improvement can be traced from the empiric testing of chemotherapeutic agents in the context of multi-institutional protocols, pre-symptomatic treatment of the central nervous system, further intensification of therapy and the use of risk adapted treatment stratification. In spite of these substantial gains, two major issues remain. First, many children are now over-treated and are thus exposed to short and long term side effects. Second, one in five children will relapse and their prognosis is poor even with aggressive retrieval strategies. Given the frequency of ALL compared to other childhood tumors, more children die from ALL each year than any other tumor. Our laboratory has utilized recent breakthroughs in high-throughput genomic technology to understand the underlying biology of ALL to refine stratification and to discover new therapeutic targets. We have identified a 47-probe set gene expression profile (GEP) that was predictive of long-term outcome on the Children’s Oncology Group High Risk ALL trial (COG-1961) as well as three large independent data sets of patients with childhood ALL who were treated on different protocols. This gene expression profile provided insight into the biologic mechanisms of treatment failure. In a related effort to discover mechanisms of relapse we have compared the GEP and copy number abnormalities (CNAs) of matched diagnosis/relapse paired samples from children also enrolled on COG trials. Relapsed blasts display increased expression of genes involved in DNA replication/repair/proliferation (e.g. TK1, RPA1, MCM2, MCM3, MCM5, MCM6, RRM1) and down regulation of genes that play a role in apoptosis (e.g. p21, TNFPAI3, RIPK2, BCLAF1, STK17B). Interestingly GEP differ among blasts from patients who relapse early while on therapy (e.g. upregulation of genes involved in mitosis) and those who relapse late (e.g. up-regulation of genes involved in nucleotide biosynthesis including the methotrexate targets DHFR and TS). We have validated survivin whose expression is uniformly increased at relapse as a therapeutic target using shRNA and antisense approaches in cell lines and in an in vivo model of ALL. Using SNP arrays we have also discovered relapse-specific CNAs including deletions of the B-cell differentiation genes IKZF1 and EBF-1 as well as MSH6, cyclin G2 and NR3C (the glucocorticoid receptor). These studies highlight the potential use of genomic approaches to stratify therapy and define more selective targets for novel therapy in the future.

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