Selective inhibition of nuclear export as a novel therapeutic strategy in AML

Current treatments for children with acute myeloid leukemia (AML) often fail to induce long-term remissions and are also toxic to normal tissues, producing serious acute and delayed sequelae in a substantial fraction of patients.  This proposal explores the therapeutic efficacy and the mechanism of action of novel CRM1 inhibitors, such as KPT-330, which appear to be highly selective anti-leukemic drugs.  My preliminary results show that these novel CRM1 inhibitors induce rapid and selective cell death in cancer cells when compared to normal cells.  This proposal focuses on defining the activity of these novel CRM1 inhibitors using human AML cells growing in mice, and the molecular basis for the observed selective killing of leukemia cells, but not normal blood cell progenitors. The knowledge gained from this study will make a significant contribution towards identifying highly active targeted treatments for AML that are less toxic to normal tissues.