Anti-Leukemic Properties of Histamine in Monocytic Leukemia: Role of NOX2

We aimed at defining effects of histamine dihydrochloride (HDC) on the maturation and expansion of monocytic acute myeloid leukemia (AML) cells in vitro and in vivo with focus on the role of the myeloid NADPH oxidase (NOX2), which is targeted by HDC acting via H₂-type histamine receptors (H₂R). The human myelomonocytic/monocytic AML cell lines PLB-985 and OCI-AML3 were found to express NOX2 and H₂R and responded to HDC with increased expression of differentiation markers and reduced cell cycle proliferation in vitro . These effects were absent in NOX2^-/- ( NOX2 -KO) PLB-985 cells. Microarray analysis revealed that HDC regulated the expression of genes involved in cell differentiation and cell cycle progression in NOX2⁺ but not in NOX2 -KO AML cells. In a xenograft mouse model using immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Sug/JicTac (NOG) mice, 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 -KO cells. Primary leukemic cells recovered from patients with monocytic forms of AML co-expressed NOX2 and H₂R and commonly upregulated the expression of the maturation markers HLA-DR, FPR1 and FPR2 after exposure to HDC. Results from a phase IV trial supported the clinical benefit of treatment with HDC, used in conjunction with low-dose IL-2, in preventing relapse among patients with monocytic forms of AML. These results imply that HDC targets NOX2 to exert anti-leukemic activity against monocytic AML cells and point towards NOX2 as a conceivable target in AML therapy.