NOX2-derived ROS in myeloid cell differentiation: Implications in cancer

Abstract

The NOX2 enzyme is highly expressed in normal myeloid cells, as well as in subpopulations of malignant myeloid cells, where it contributes to the generation of reactive oxygen species (ROS). We have utilized mice and leukemic cells genetically depleted of NOX2 and the NOX2-specific inhibitor histamine dihydrochloride (HDC) to further elucidate the role of NOX2-derived ROS in hematopoietic cancer. HDC was found to promote the maturation of human DCs from monocytes and to enhance T cell priming. In addition, treatment of mice with HDC reduced the growth of murine EL-4 lymphomas in parallel with an increment of tumor-infiltrating DCs in NOX2-sufficient mice but not in Nox2-/- mice. HDC was also found to facilitated the maturation and inhibit the proliferation of NOX2-expressing human acute myeloid leukemia (AML) cells. These effects were absent in NOX2-/- AML cells. In microarray analysis, HDC was found to regulate the expression of genes involved in cell differentiation and cell cycle progression in NOX2+ but not in NOX2-/- AML cells. In a xenograft mouse model, systemic treatment with HDC reduced the expansion of engrafted monocytic AML cells in bone marrow but did not exert anti-leukemic activity against engrafted NOX2-/- AML cells.