NUCLEOTIDE EXCISION REPAIR (NER) IN ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) AS APREDICTOR OF EARLY RELAPSE

Melnick Auditorium

Objective. To determine whether expression of NER DNA repair genes affects development of drug resistance and relapse in ALL. Background. Relapse in ALL is associated with the development of resistance to primary therapy. NER is a metabolic pathway that protects cells from the effects of genotoxic agents, such as chemotherapy drugs. Methods. We studied the role of NER in ALL by secondary analysis of 2 independent gene expression microarray studies: Staal et al. (Set A) and Hogan et al. (Set B). Both studies analyzed matched diagnosis-relapse leukemic cells of ALL patients (41 and 49 pairs, respectively). Results. In Set A we found that 17/20 NER genes were overexpressed at time of relapse, 4 of which were individually significantly increased: ERCC1, ERCC8, ERCC4 and DDB1. Subset analysis of Set B, based on patients who have early ( < 3 years) vs. late ( > 3 years) relapse gave distinct results. NER gene expression at the time of diagnosis of patients in the early relapse group was increased in all 20 NER genes when compared to the late group (p=0.001). 7 genes showed individually significant increases in expression: XPE, DDB1, RPA3, RPA2, ERCC2, ERCC1 and ERCC8. In Set A, 18/20 NER genes were upregulated at the time of diagnosis in early relapse patients vs. the late group. 4 genes were significantly increased: RPA1, CCNH, DDB1 and RPA2. Conclusion. We have discovered that early relapse in ALL is associated with elevated NER gene expression at the time of diagnosis. Pharmacogenomic targeting of such patients might include dose escalation. Grants. Children's Leukemia Research Association