Do reactive oxygen species play a role in myeloid leukemias?

Abstract

Reactive oxygen species (ROS) are a heterogeneous group of molecules that are generated by mature myeloid cells during innate immune responses, and are also implicated in normal intracellular signaling. Excessive production of ROS (and/or a deficiency in antioxidant pathways) can lead to oxidative stress, a state that has been observed in several hematopoietic malignancies including acute and chronic myeloid leukemias (AML and CML). Currently it is unclear what the cause of oxidative stress might be and whether oxidative stress contributes to the development, progression, or maintenance of these diseases. This article reviews the current evidence suggesting a role for ROS both in normal hematopoiesis and in myeloid leukemogenesis, and discusses the usefulness of therapeutically targeting oxidative stress in myeloid malignancy. (Blood. 2011;117(22):5816-5826) IntroductionOver the past 15 years, there has been a growing appreciation that reactive oxygen species (ROS) production plays an important role in a variety of cellular processes, in addition to their antimicrobial role during phagocytosis by cells of the innate immune system. Specifically, ROS generated by the mitochondria or nicotinamide adenine dinucleotide phosphate (NADPH) oxidases have been shown to influence cell-cycle progression, cell motility, and growth factor signaling in a variety of normal cell types. 1 Many pathologic states are accompanied by excessive cellular ROS production and/or a deficiency in antioxidant defenses, leading to a state known as oxidative stress. 2 Evidence for chronic oxidative stress has been found in many cancers, both in solid tumors such as prostate carcinoma 3 and melanoma 4 and in several hematopoietic malignancies including acute lymphoblastic leukemia (ALL), 5 myelodysplastic syndrome (MDS), 6 and myeloid leukemias including chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). 7 The importance of the association between oxidative stress and malignancy is not currently clear; however, there is evidence that tumor-derived ROS may promote cell survival, 8-10 migration and metastasis, 11,12 proliferation, 13,14 and even drug-resistance, 15 depending on the origin of the cancer. These observations suggest that oxidative stress may subvert the normal roles of ROS so as to benefit the malignant clone.In the context of AML, a recent report indicates that relapse in this disease is associated with increased markers of oxidative stress within the leukemic blasts, suggesting that ROS production may be an important factor in AML progression. 16 Indeed, recent published data from our group suggest that constitutively active Ras (one of the most common abnormalities detected in AML) is capable of driving ROS production in CD34 ϩ human hematopoietic progenitor cells, and this significantly contributes to the mutant Ras phenotype. 17 Furthermore, ROS production appears to contribute to proliferation and migration of hematopoietic cells expressing a variety of oncogenic tyrosine kinases. 18 Thus, increased oxidative s...

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

“…Thus, new therapies that more specifically target the molecular or metabolic abnormalities within leukemic cells have been highly sought. 28,29 In this study, we show that the mutation of W288 to cysteine sensitizes cells to oxidative stress induced by both bortezomib and ATO. In addition, the specific acquisition of a cysteine residue at position 288 appears to be responsible for the cytoplasmic accumulation of the most common variants of NPMc þ that contain the W288C mutation.…”

“…9,23 Arsenic trioxide (ATO) has emerged as the most active single agent in the treatment of acute promyelocytic leukemia, 24 and ATO-based therapies are being investigated in other cancers including other hematopoietic malignancies. [25][26][27][28][29] Although the mechanisms underlying ATO-induced cytotoxicity are not completely understood, ATO-mediated induction of ROS has been shown to reduce the membrane potential of mitochondria, enhance the release of cytochrome c and induce both caspasedependent and caspase-independent apoptosis. [30][31][32] AML has a poor prognosis in older patients, and intensive induction carries high morbidity and significant mortality.…”

NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

“…Increased ROS levels upon cytokine stimulation; low PRDX2 levels correlated with poor prognosis [29] A plethora of data has indicated alterations in ROS metabolism in leukemia, either linked to etiology, prognosis or therapy responses [30,31]. Many studies have supported the idea that ROS formation M A N U S C R I P T…”

NADPH Oxidase-generated Hydrogen Peroxide Induces DNA Damage in Mutant FLT3-expressing Leukemia Cells

“…It was also demonstrated that cells expressing the ITD-mutated FLT3 generate higher levels of ROS (11)(12)(13). ROS, for example, H 2 O 2 , are considered to play an important role in cancers, including leukemia (14,15). Due to their DNA damaging properties, they are known to contribute to genomic instability.…”