Abstract PR09: APOBEC3A sensitizes leukemia cells to inhibitors of the replication checkpoint

The human APOBEC3 family of DNA-cytosine deaminases comprises seven members (A3A-A3H) that act on single-stranded DNA (ssDNA). The APOBEC3 enzymes are best defined by their capacity to restrict viral infection, however several family members are also capable of causing cellular DNA damage that leads to activation of DNA damage responses. Mutational signatures consistent with APOBEC3 activity have been identified in cancer genomes, and elevated expression of APOBEC3 enzymes has been observed in solid tumors. These findings point to a role for APOBEC3 enzymes in cancer-associated mutagenesis, however the impact of APOBEC3 activity within cancer cells has not been examined to date. We hypothesized that A3A is a potential source of mutagenesis in leukemia, since it is endogenously expressed at high levels in hematopoietic cells. To identify hematologic malignancies in which A3A expression is elevated, we examined RNA sequencing from adult and pediatric leukemias in the TCGA and TARGET databases. We found elevated A3A expression in a subset of pediatric and adult acute myeloid leukemia (AML). Additionally, we found that high A3A expression was associated with decreased survival, suggesting that new therapeutic options are important for patients with this type of malignancy. Since we have previously demonstrated that A3A acts on the cellular genome during replication, we hypothesized that abrogation of the replication checkpoint will produce genotoxicity and cell death in leukemias...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Proffered Abstracts Source Type: research