Androgen receptor signaling as a new target for intervention in acute myeloid leukemia

In addition to their role in development, sex hormones and their cognate receptors play an important role in various malignancies. Using a murine model of human mixed lineage leukemia-acute leukemia fused gene from chromosome 9 (MLL-AF9)-induced acute myeloid leukemia (AML), we discovered that high androgen receptor (AR)-expressing leukemia initiating cells (LICs), when transferred into either male or female recipients, produced more severe disease than low AR-expressing LICs. AR expression was significantly increased in female LICs when compared with male LICs. This difference was confined to the LICs and was not present in normal bone marrow cells. AML cells from both sexes relied on AR signaling via different mechanisms; females had high AR levels with low ligand levels and males had low AR levels with high ligand levels. AR expression was linked to the ephrin type-A receptor 7 (EPHA7)-associated PI3K/AKT/mTOR and SRC/HIF-1α pathways. The use of the 2 United States Food and Drug Administration-approved drugs for prostate cancer, namely ARN509, an AR antagonist, and finasteride, which inhibits the pathway that produces dihydrotestosterone, led to significant remission with increased survival of the AML mice. ARN509 and finasteride also showed proapoptotic effects in patient-derived AML cells and in a humanized AML NOD scid gamma (NSG) mouse model. These data support a drug repurposing effort for the use of antiandrogen therapy to improve the efficacy of AML treatments.