Abstract
Cytosolic release of histone H1.2 has been described as a new apoptogenic mechanism induced by DNA damage that results in cytochrome C release and activation of the apoptotic mitochondrial pathway. Primary tumoral CLL cells from 25 patients were investigated for histone H1.2 cytosolic release after treatment with genotoxic (fludarabine, mitoxantrone, etoposide, or X-ray radiation) and non-genotoxic (dexamethasone) agents. Cases were analyzed for the presence of poor-risk genetic alterations, particularly deletions at 17p13 and 11q22. Histone H1.2 release was correlated with the presence of genetic abnormalities and with the best clinical response obtained with standard treatments. FISH analysis, cell viability measured by annexin V binding, Western Blot studies and inmunofluorescence techniques with confocal spectral microscopy were also employed. DNA-damaging agents induced H1.2 release in a p53-dependent manner, which was confirmed by the lack of H1.2 release in p53-deleted cases. Non DNA-damaging agents induced release of H1.2 in both p53-deleted and non-deleted CLL cases. Moreover, nuclear H1.2 release was observed after genotoxic and non-genotoxic treatment independently of ATM function. From the clinical standpoint, the lack of histone H1.2 release correlated with resistance to genotoxic treatment. In CLL cells, histone H1.2 traffic was dependent on the p53-status after genotoxic treatment, but was also inducible after treatments acting independently of p53. In contrast, histone H1.2 release seemed not to be dependent on ATM function. Nuclear histone H1.2 release appears to be an important element in apoptosis induction in CLL, particularly in cases with abnormal p53 function resistant to conventional treatment.
Author notes
Disclosure: No relevant conflicts of interest to declare.
