Reactive Oxygen Species in Acute Lymphoblastic Leukaemia: Reducing Radicals to Refine Responses

Abstract

Acute lymphoblastic leukaemia (ALL) is the most common cancer diagnosed in children and adolescents. Approximately 70% of patients survive >5-years following diagnosis, however, for those that fail upfront therapies, survival is poor. Reactive oxygen species (ROS) are elevated in a range of cancers and are emerging as significant contributors to the leukaemogenesis of ALL. ROS modulate the function of signalling proteins through oxidation of cysteine residues, as well as promote genomic instability by damaging DNA, to promote chemotherapy resistance. Current therapeutic approaches exploit the pro-oxidant intracellular environment of malignant B and T lymphoblasts to cause irreversible DNA damage and cell death, however these strategies impact normal haematopoiesis and lead to long lasting side-effects. Therapies suppressing ROS production, especially those targeting ROS producing enzymes such as the NADPH oxidases (NOXs), are emerging alternatives to treat cancers and may be exploited to improve the ALL treatment. Here, we discuss the roles that ROS play in normal haematopoiesis and in ALL. We explore the molecular mechanisms underpinning overproduction of ROS in ALL, and their roles in disease progression and drug resistance. Finally, we examine strategies to target ROS production, with a specific focus on the NOX enzymes, to improve the treatment of ALL.

Blockade of redox second messengers inhibits JAK/STAT and MEK/ERK signaling sensitizing FLT3-mutant acute myeloid leukemia to targeted therapies

“…Hyperactivated AMKK-AMPK signaling was the next top ranked kinase pathway in FLT3-ITD mutant AML; an intriguing result given that AMPK protects leukemia initiating cells (LICs) from metabolic and oxidative stressors (27). ABR kinase was also predicted to be hyperactivated, and when phosphorylated known to accelerate GTP hydrolysis of RAC1 or CDC42 to drive ROS production and drive oxidative stress (28), providing phosphoproteomic clues into the oxidative dysregulation of leukemia cells harboring kinase activating mutations (9,10). INKA analysis of hyperactivated kinases in patient samples harboring wt-FLT3 showed a comparatively benign kinase signature, however also identified additional discrete components of AMPK signaling, and the core Hippo kinase STK4 (MST1) (29) as being hyperactivated (Supplementary Fig.…”

“…Despite a rapid growth in knowledge of the genomic landscapes of AML, the condition remains a devastating disease with a poor prognosis (54). Among the alternative underlying etiologies that could contribute to this condition, ROS are emerging as key regulators of cellular signaling pathways, including those implicated in driving leukemogenesis (9,14,19,46,55). Thus, therapeutic manipulation of cellular ROS levels may hold promise as a novel treatment approach in AML (10).…”

“…FLT3 inhibitors have recently been approved for use in FLT3-mutant AML patients, however improvements in outcomes are modest with relapse rates high (2,6). There is growing evidence that reactive oxygen species (ROS) promote leukemogenesis (7), indeed, it is well recognized that ROS play a critical role in regulating normal hematopoiesis (8,9). Oncogenic driver mutations are strongly linked to increased ROS production in myeloid malignancies (10).…”

High-Throughput Global Phosphoproteomic Profiling Using Phospho Heavy-Labeled-Spiketide FAIMS Stepped-CV DDA (pHASED)

“…One potent mechanism of increased DSBs is via the excess production of reactive oxygen species (ROS). Increased ROS production by the NADPH oxidase (NOX) family of enzymes in acute leukemias, particularly FLT3-ITD AML, has been increasingly studied over the last few years, and highlights that elevated ROS is a mechanism conferring survival advantages in FLT3-mutant AML (47–50). Given ATM signaling was predicted to be one of the top ranked canonical pathways driving the DNA damage repair and response pathways in resistant cells (Fig.…”

Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone‐Thienopyrimidine Derivatives in HepG2 and MCF‐7 Cell Lines

“…High levels of ROS, such as hydrogen peroxide, superoxide, and hydroxyl radicals, have been shown to cause cell cycle arrest, apoptosis, and irreversible cell damage in cancer cells [ 23 ]. Besides, excessive quantities of ROS oxidize and nitrate macromolecules such as lipids, proteins, and DNA, resulting in significant cellular damage [ 24 ].…”