Our major findings are: 1) Gene expression analysis reflects an antioxidant and defensive cellular response to ATO; 2) ATO strongly upregulates HMOX1 and, to a lesser extent, MMP-9; 3) The mechanism by which ATO upregulates MMP-9 is via activation of the p38 MAPK/AP-1 pathway; 4) HMOX1 interferes with p38 MAPK/AP-1 activation and downregulates MMP-9; 5) HMOX1 exerts a pro-apoptotic role in CLL cells in response to ATO, synergistically enhancing the cytotoxicity of this agent. The gene discussed is HMOX1; the disease is B-cell chronic lymphocytic leukemia.