Functional Pharmacogenomics of Childhood Acute Lymphoblastic Leukemia in Taiwan

Emerging results suggest that a cure rate of nearly 90 percent will be attained in the near future. The advance was attributed to stringent application of prognostic factors for risk factor-directed therapy. Early response to treatment has greater prognostic strength than does any other biologic or clinical feature tested to dates. The measurement of minimal residual disease(MRD) affords a level of sensitivity and specificity that cannot be attained through traditional microscopic morphologic assessments. In Taiwan, detection for the most recurrent fusion genes and the MRD were not commonly available, the TPOG(Taiwan Pediatric Oncology Group) used clinical features, immunophenotypes, and cytogenetics to do risk group classifications and protocol assignment. A successful rate of 60-70% has been reached. In order to improve the cure rate of ALL in Taiwan, this project aims at establishing the methods for better risk classifications and establishing MRD detection for risk-directed therapy for childhood ALL in Taiwan.Intrinsic and acquired resistances to multiple anticancer agents represent major obstacles and accounts for 10-20% of treatment failure in the developed countries nowadays. Recent progress using DNA microarray identified differential expression level of the genes known to implicate in cell cycle control, DNA repair and apoptosis in different subsets of ALL patients, which were found to be related to drug response. Genetic polymorphisms in the genes of drug-metabolizing enzymes, drug transporters or drug targets, can influence the efficacy or toxicity of antileukemic agents. Specific genotype might be important in determining the pharmacokinetic effects of one population or disease subtype from that in others. Recently, the expression profiles of relatively few microRNAs (miRNAs) (\~200 genes), was noted to accurately classify human cancers. These informations hinted that expression of the genes in the leukemic cells might serve as additional risk factors for treatment stratification. Specific aims and goals: 1. to establish better risk factors classification and use MRD to monitor early response to treatment. 2. to establish the expression profiles of 12 genes associated with drug resistance 3. to unravel the pharmacogenetic background of pediatric ALL in Taiwan, so that will help refine the therapy dose, achieve a better drug effect and avoid acute or chronic toxicity. 4. microRNA expression profiles in childhood ALL in Taiwan