Reactive oxygen species (ROS) were seen as destructive molecules, but recently, they have been shown also to act as second messengers in varying intracellular signaling pathways. This review concentrates on hydrogen peroxide (H2O2), as it is a more stable ROS, and delineates its role as a survival molecule. In the first part, the production of H2O2 through the NADPH oxidase (Nox) family is investigated. Through careful examination of Nox proteins and their regulation, it is determined how they respond to stress and how this can be prosurvival rather than prodeath. The pathways on which H2O2 acts to enable its prosurvival function are then examined in greater detail. The main survival pathways are kinase driven, and oxidation of cysteines in the active sites of various phosphatases can thus regulate those survival pathways. Regulation of transcription factors such as p53, NF-kappaB, and AP-1 also are reviewed. Finally, prodeath proteins such as caspases could be directly inhibited through their cysteine residues. A better understanding of the prosurvival role of H2O2 in cells, from the why and how it is generated to the various molecules it can affect, will allow more precise targeting of therapeutics to this pathway.

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Bcr-Abl causes chronic myelogenous leukemia, a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells. In this study, inducible expression of Bcr-Abl in TonB.210 cells is associated with increased production of intracellular reactive oxygen species (ROS), which is thought to play a role in survival signaling when generated at specific levels. Elevated ROS in Bcr-Abl-expressing cells were found to activate PI3k/Akt pathway members such as Akt and GSK3b as well as downstream targets b-catenin and Mcl-1. The activation of these proteins was inhibited by the flavoprotein inhibitor diphenyleneiodonium, which is commonly used to inhibit NADPH oxidase (Nox). This indicated that increased ROS might be related to increased activity of one member of the Nox family. Knock-down experiments using siRNA suggest that Nox-4 is the main source of increased ROS following Bcr-Abl expression. We showed that Bcr-Abl-induced ROS could also increase survival pathway signaling through redox inhibition of PP1a, a serine threonine phosphatase that negatively regulates the PI3k/Akt pathway. Overall our results demonstrate that Bcr-Abl expression increases Nox-4-generated ROS, which in turn increases survival signaling through PI3k/Akt pathway by inhibition of PP1a, thus contributing to the high level of resistance to apoptosis seen in these Bcr-Abl-expressing cells.

SummaryB-cell chronic lymphocytic leukaemia (B-CLL) is the most prevalent leukaemia in Western countries and is characterized by the gradual accumulation in patients of small mature B cells. Since the vast majority of tumoral cells are quiescent, the accumulation mostly results from deficient apoptosis rather than from acute proliferation. Although the phenomenon is relevant in vivo, B-CLL cells die rapidly in vitro as a consequence of apoptosis, suggesting a lack of essential growth factors in the culture medium. Indeed, the rate of B-CLL cell death in vitro is modulated by different cytokines, some favouring the apoptotic process, others counteracting it. Two related members of the tumour necrosis factor family, BAFF (B-cell activating factor of the TNF family) and APRIL (a proliferationinducing ligand), already known for their crucial role in normal B-cell survival, differentiation and apoptosis, were recently shown to be expressed by B-CLL cells. These molecules are able to protect the leukaemic cells against spontaneous and drug-induced apoptosis via autocrine and/or paracrine pathways. This review will focus on the role of BAFF and APRIL in the survival of tumoral cells. It will discuss the expression of these molecules by B-CLL cells, their regulation, transduction pathways and their effects on leukaemic cells. The design of reagents able to counteract the effects of these molecules seems to be a new promising therapeutic approach for B-CLL and is already currently developed in the treatment of autoimmune diseases.