Initiation and progression of cancer is regulated by a multistage process linked to the production of reactive oxygen species (ROS). Patients diagnosed with recurring mutations to the FMS-like tyrosine kinase-3 (FLT3), a receptor tyrosine kinase mutated in 1/3rd of all acute myeloid leukaemia (AML) patients has a high rate of relapse and a poor prognosis. FLT3-ITD (Internal Tandem Duplication) mutations are associated with the overproduction of ROS which is linked to increased genomic instability through the oxidation of DNA bases. We sought to determine the cooperative mechanisms between phosphorylation and oxidation in these patients to help us understand how chemical modifications affects the growth and survival of these cells. Bone marrow derived mononuclear cells from 16 AML patients were subjected to targeted next-generation sequencing and high-resolution proteomic analysis. High-resolution proteomics facilitated the quantification of 2,678 unique phosphoproteins and 4,029 proteins showing oxidisation across 16 samples. Interestingly, patients expressing FLT3-ITD mutations (n=6) showed significantly increased oxidation of tumour suppressor proteins compared to patients expressing wild-type FLT3 (n=6). Significant activation of the oncogenic kinases; SRC, MAPK and AKT were observed along with pathways responsible for error-prone DNA-repair. Interestingly, proteins important in maintaining cellular homeostasis, such as antioxidants were differentially regulated between patient subtypes supporting the notion of REDOX dysfunction in ITD+ patients. Repositioned drugs were used to target these pathways. FLT3-ITD AML cells were highly sensitive to pharmacological inhibition of REDOX signalling pathways and DNA-repair. The inhibition of pathways responsible for the overproduction of ROS selectively sensitised FLT3-ITD cells to standard AML chemotherapies. In vivo mouse models are currently testing the clinical utility of our novel treatment strategy. For the first time we reveal how a recurring genetic mutation to an oncogenic kinase increases oxidative stress, damages DNA which leads to increased genomic instability and influence the commonly observed resistance to therapies.