Ectopic viral integration site-1 (evi1)-mediated repression of carbonic anhydrase iii (caiii) and its implications: role in acute myeloid leukaemia

Ectopic viral integration site-1 (EVI1) is a nuclear zinc finger protein whose increased expression has been associated with poor prognosis in cases of Acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). In this study, we showed that expression of EVI1 in Rat fibroblast cells represses carbonic anhydrase III (CAIII), which is involved in protecting cells from oxidative damage. Reporter assays showed that the CAIII promoter activity is 7 times stronger in the absence of enforced expression of EVI1. This demonstrated that the EVI1-mediated repression of CAIII occurred at the level of transcription and could either be due to a direct repression or an indirect repression of the CAIII gene promoter by EVI1. We also showed that CAIII protects cells from apoptosis induced by oxidative stress by knocking down CAIII with Dicer-substrate short inhibitory RNAs and treating CAIII¬-knockdown cells with hydrogen peroxide (H2O2). This suggests that EVI1-mediated repression of CAIII may expose cells to death due to oxidative damage by reactive oxygen species (ROS). We conclude that EVI1 represses expression of CAIII at transcriptional level and exposes cells to death by oxidative agents. Taken together, this study provides a possible therapeutic approach of using oxidizing drugs to target disease cells such as in AML with increased expression of EVI1.