Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies

Mutations in the type III receptor tyrosine kinase FLT3 are frequent in patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is characterized by the overproduction of reactive oxygen species (ROS), which can induce cysteine oxidation in redox-sensitive signaling proteins. Here, we sought to characterize the specific pathways affected by ROS in AML by assessing oncogenic signaling in primary AML samples. The oxidation or phosphorylation of signaling proteins that mediate growth and proliferation was increased in samples from patient subtypes with FLT3 mutations. These samples also showed increases in the oxidation of proteins in the ROS-producing Rac/NADPH oxidase-2 (NOX2) complex. Inhibition of NOX2 increased the apoptosis of FLT3-mutant AML cells in response to FLT3 inhibitors. NOX2 inhibition also reduced the phosphorylation and cysteine oxidation of FLT3 in patient-derived xenograft mouse models, suggesting that decreased oxidative stress reduces the oncogenic signaling of FLT3. In mice grafted with FLT3 mutant AML cells, treatment with a NOX2 inhibitor reduced the number of circulating cancer cells, and combining FLT3 and NOX2 inhibitors increased survival to a greater extent than either treatment alone. Together, these data raise the possibility that combining NOX2 and FLT3 inhibitors could improve the treatment of FLT3 mutant AML. Description Inhibiting the ROS-generating Rac-NOX2 complex delays the progression of FLT3 mutant acute myeloid leukemia. Blocking NOX2 bolsters AML precision therapy Internal tandem duplication of Fms-like tyrosine kinase 3 (FLT3-ITD) is a common activating mutation in acute myeloid leukemia (AML) and leads to the increased production of reactive oxygen species (ROS). AML patients on FLT3-targeting therapies have a high rate of relapse. By performing a proteome-wide analysis of cysteine oxidation and phosphorylation of AML blast cells from patients harboring FLT3 mutations, Germon et al. identified the Rac-NOX2 complex as a driver of ROS production in AML cells. Inhibition of NOX2 promoted apoptosis of AML cells carrying the FLT3-ITD mutation and increased the survival of mice grafted with FLT3-ITD AML cells and treated with FLT3 inhibitors. Thus, targeting NOX2 may increase the effectiveness of precision therapy targeting AML. —AB