5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-Mediated Apoptosis

PURPOSE: Patients with acute myeloid leukemia (AML) frequently do not respond to conventional therapies. Leukemic cell survival and treatment resistance have been attributed to the overexpression of B-cell lymphoma 2 (BCL-2) and aberrant DNA hypermethylation. In a phase Ib study in elderly patients with AML, combining the BCL-2 selective inhibitor venetoclax with hypomethylating agents 5-azacitidine (5-Aza) or decitabine resulted in 67% overall response rate; however, the underlying mechanism for this activity is unknown. EXPERIMENTAL DESIGN: methods to understand their respective roles in driving the venetoclax/5-Aza combinatorial activity. RESULTS: knockout confirmed its major role in driving venetoclax and 5-Aza synergy. CONCLUSIONS: .