Homo sapiens Genome sequencing. Homo sapiens

ROS-dependent up-regulation of p53 in proliferating chronic lymphocytic leukemia cellsIn Chronic Lymphocytic Leukaemia (CLL), proliferation and apoptosis occur indifferent anatomical compartments. Cells multiply and are more resistant to immunochemotherapyin “proliferation centers” within tissues, whereas apoptosis occurs inthe periphery in the absence of such signals. Various models recapitulate thesemicroenvironments in vitro, such as CD154/IL4 stimulation. Using this system, weobserved that >50% of CLL cells undergo proliferation after 72h. Unexpectedly, a 30-40 fold induction of wild-type p53 was observed in all 50 analyzed cases, withoutinduction of either cell cycle arrest or apoptosis. Instead, p53 expression wasassociated with cell proliferation. p53 mRNA levels were not induced in stimulatedcells, indicating that elevation of p53 occurred post-transcriptionally. The upregulatedp53 protein was phosphorylated in key residues and its half-life wasincreased, but it was capable of transcriptionally activating only a subset of its targetgenes. In contrast, DNA damaging agents further up-regulated p53 levels, which thenresulted in apoptosis. Of note, induction of p53 and proliferation was dependent onthe increase in intracellular reactive oxygen species (ROS) observed after CD154/IL43stimulation. In view of these results, we propose that the microenvironment inproliferation centers induces a chronic oxidative stress in CLL B-cells capable ofelevating the basal expression of p53 to levels that are below the threshold to inducearrest or apoptosis in these cells, but may paradoxically contribute to proliferation.Reactivation of the full transcriptional activities of p53 in proliferating CLL cells mayprovide new therapeutic approaches.