BET Bromodomain inhibition promotes De-repression of TXNIP and activation of ASK1-MAPK pathway in acute myeloid leukemia

Abstract

Abstract Background Targeted therapy has always been the focus in developing therapeutic approaches in cancer, especially in the treatment of acute myeloid leukemia (AML). A new small molecular inhibitor, JQ1, targeting BRD4, which recognizes the acetylated lysine residues, has been shown to induce cell cycle arrest in different cancers by inhibiting MYC oncogene. However, the downstream signaling of MYC inhibition induced by BET inhibitor is not well understood. Methods In this study, we explored the more mechanisms of JQ1-induced cell death in acute myeloid lukemia and downstream signaling of JQ1. Results We found that JQ1 is able to reactivate the tumor suppressor gene, TXNIP, and induces apoptosis through the ASK1-MAPK pathway. Further studies confirmed that MYC could repress the expression of TXNIP through the miR-17-92 cluster. Conclusions These findings provide novel insight on how BET inhibitor can induce apoptosis in AML, and further support the development of BET inhibitors as a promising therapeutic strategy against AML.