Base Excision Repair Deficiency in Acute Myeloid Leukemia.

Abstract 1106

Poster Board I-128

Base excision repair (BER) is the main DNA repair mechanism for single DNA base lesions resulting from oxidative stress, chemical damage or ionizing radiation. We investigated BER in acute myeloid leukemia (AML), a disorder characterized by widespread genomic instability. AML cell lines were treated with H2O2 and DNA damage induction and repair were monitored using the alkaline comet assay. Significantly reduced single strand break (SSB) formation - representing BER intermediates - was observed in 5/10 cell lines. Significantly reduced SSB formation was also demonstrated in 15/30 leukemic samples from patients with therapy-related AML, 13/35 with de novo AML and 14/26 with AML following a myelodysplastic syndrome but only in 1/31 CD34+ hematopoietic stem and progenitor cell specimens isolated from umbilical cord blood (P=.0000056). Reduced SSB formation was not due to differences in intracellular ROS concentrations or selection for a damage resistant subpopulation. To determine whether initial steps of BER were impaired, incision assays with oligonucleotides harboring either 7,8-dihydro-8-oxoguanine or the AP site analog furan were performed. Significantly diminished cleavage for both substrates was observed in cell lines that did not exhibit SSB formation upon H2O2 treatment. These data demonstrate that BER is functionally impaired in a significant proportion of myeloid cell lines and leukemic cells from patients with AML.