Protein Phosphorylation and Redox Status: An as Yet Elusive Dyad in Chronic Lymphocytic Leukemia

SIMPLE SUMMARY: Phosphorylation is one of the most crucial modifications of lipids and proteins, as it regulates virtually all cellular functions. Like other human diseases, chronic lymphocytic leukemia (CLL), the most common leukemia in Western developed countries, exhibits deranged phosphorylation, which is induced by stimuli within specific tissues (e.g., lymph nodes), promoting enhanced proliferation and survival. Importantly, a growing body of evidence shows that reactive oxygen species (ROS), altered forms of oxygens generated from metabolism and peculiar enzyme complexes, and generally considered highly harmful due to their reactivity toward critical biomolecules (proteins, lipids, and DNA), act in concert with phosphorylation in supporting the malignant phenotype in CLL. This complex interplay is now providing insights into potential novel Achilles heels of intracellular signals for the development of innovative treatments which might synergize with the drugs currently in use that target the principal players in phosphorylation, namely kinases. ABSTRACT: Malignant cells in chronic lymphocytic leukemia (CLL) are characterized by oxidative stress that is related to abundant generation of reactive oxygen species (ROS) by increased mitochondrial oxidative phosphorylation (OXPHOS). Lymphoid tissues have been shown to provide a protective microenvironment that antagonizes the effects of ROS, contributing to establishing redox homeostasis that supports the vitality of CLL cells. In the last few decades, a complex antioxidant machinery has been demonstrated to be activated in CLL cells, including the different superoxide dismutase (SOD) isoforms, the thioredoxin (Trx) system, and the enzyme cascade inducing glutathione (GSH) biosynthesis and recycling, to name a few. Their expression is known to be upregulated by the activation of specific transcription factors, which can be regulated by either oxidative stress or phosphorylation. These two latter aspects have mostly been explored separately, and only recently an increasing body of evidence has been providing reasonable inference that ROS and phosphorylation may cooperate in an interplay that contributes to the survival mechanisms of CLL cells. Here, we present an overview of how oxidative stress and phosphorylation-dependent signals are intertwined in CLL, focusing on transcription factors that regulate the balance between ROS production and scavenging.