Gain of function (GOF) mutations in protein tyrosine phosphatase Ptpn11 have been identified in childhood leukemias, and these mutations are sufficient to drive the development of myeloproliferative disorder and malignant leukemias in mice. However, the molecular mechanisms by which Ptpn11 mutations induce these malignancies are not completely understood. Here we report that Ptpn11 GOF mutations cause cytokine hypersensitivity in hematopoietic cells partly by enhancing the production of reactive oxygen species (ROS). GOF mutations D61G or E76K in Ptpn11 increased ROS levels in myeloid progenitors but not in hematopoietic stem cells. Increased ROS enhanced cellular responses to cytokines by promoting cytokine signaling. Treatment with an antioxidant partially corrected cytokine hypersensitivity in Ptpn11 mutant progenitors. Further analyses demonstrated that Ptpn11 mutations increased mitochondrial aerobic metabolism by interacting with a novel substrate in the mitochondria. This study provides new insights into the pathogenic effects of GOF mutations of Ptpn11 and implies that antioxidants may have a therapeutic benefit for the leukemic patients with these mutations.