ELEVATED EXPRESSION OF NUCLEOTIDE EXCISION REPAIR GENES UPON RELAPSE OF ACUTE LYMPHOCYTIC LEUKEMIA

Atrium

Objective. The overall goal of this project is to assess the role of Nucleotide Excision Repair (NER) in pediatric Acute Lymphocytic Leukemia (ALL) relapse using genomic methods. We hypothesize that ALL relapse in the patient, after a period of remission driven by primary chemotherapeutic treatment with genotoxic chemotherapy agents, will show increased expression of NER genes and therefore increased capacity for repairing DNA damage. Background. Deficiencies in NER genes are responsible for the hereditary cancer-prone diseases xeroderma pigmentosum and Cockayne syndrome, and we have previously demonstrated functional and molecular alteration of this pathway in breast cancer. Methods. We performed a detailed analysis of gene expression microarray data from 41 matched primary and relapsed pediatric ALL samples from colleagues in the Netherlands. We analyzed expression data for the 20 canonical NER (a.k.a. “long-patch” DNA repair) genes. Results. Our findings demonstrate that 18 of the 20 genes studied had higher expression in the relapsed samples (P = 0.003). Six genes showed an individual significant increase in gene expression, CCNH (P = 0.020), DDB1 (P = 0.026), CSA (P = 0.033), ERCC1 (P = 0.015), hHRAD23B (P = 0.039), and CDK7 (P = 0.012), with two additional genes very close to statistical significance, XPB (P = 0.094) and RPAp70 (P = 0.080). Conclusion. These data are similar to what we have found in breast tumors of increasing stage, and are consistent with the idea that relapsing neoplastic disease is inherently capable of greater DNA repair, resulting in functional drug resistance. Grants. This work was supported by a grant from the National Children's Leukemia Research Association to JJL.