Data from NF-κB–Inhibited Acute Myeloid Leukemia Cells Are Rescued from Apoptosis by Heme Oxygenase-1 Induction

Despite high basal NF-κB activity in acute myeloid leukemia (AML) cells, inhibiting NF-κB in these cells has little or no effect on inducing apoptosis. We previously showed that heme oxygenase-1 (HO-1) underlies this resistance of AML to tumor necrosis factor–induced apoptosis. Here, we describe a mechanism by which HO-1 is a silent antiapoptotic factor only revealed when NF-κB is inhibited, thus providing a secondary antiapoptotic mechanism to ensure AML cell survival and chemoresistance. We show that inhibition of NF-κB increased HO-1 expression in primary AML cells compared with that of nonmalignant cells. In addition, we observed this suppressed HO-1 level in AML cells compared with CD34⁺ nonmalignant control cells. Using chromatin immunoprecipitation assay and small interfering RNA knockdown, we showed that the NF-κB subunits p50 and p65 control this suppression of HO-1 in AML cells. Finally, we showed that inhibition of HO-1 and NF-κB in combination significantly induced apoptosis in AML cells but not in noncancerous control cells. Thus, NF-κB inhibition combined with HO-1 inhibition potentially provides a novel therapeutic approach to treat chemotherapy-resistant forms of AML. Cancer Res; 70(7); 2973–83