VP16 hypersensitivity and increased faulty recombination in ataxia telangiectasia lymphocytes characterizedby the tandem translocation t(14; 14)(q11;q32)

Ataxia telangiectasia (AT) patients show variable degrees ofimmunodeficiency and a higher than normal predisposition tolymphoid malignancies. At cells are characterized by spontaneouschromosome instability resulting in chromosome breakageand innon random chromosome rearrangements. Sequential cytogeneticstudies on T-lymphocytes from an AT patient showed theprogressivedevelopment of a clone bearing a tandem translocation t(14;14)(q11;q32). The abnormal clone had spontaneous chromosomerearrangements. Compared to non clonal cells, the abnormal clonedisplayed a higher frequency of spontaneous chromosome rearrangements.In only the clonal cells we observed two particular and predominantrearrangements: isodicentric chromosomes and telomeric associationswhich may derive from faulty recombination. Chromosome instabilityinduced by the etoposide VP16, a DNA topoisomerase II inhibitor,was evaluated in terms of chromosome breakage and SCE frequency.T-lymphocytes from the AT patient showed hypersensitivity toVP16 significantly higher than normal T-lymphocytes. The chromosomeinstability induced by VP16 is significantly higher in clonalthan in non clonal cells, whilst the chromosome instabilityinduced by the radiomimetic drug bleomycin is not significantlydifferent in the two AT lymphocyte subpopulations. The differentspontaneous chromosome instability in clonal and non clonalcells together with their different behavior after treatmentwith only VP16, suggest that clonal cells bearing the tandemtranslocation could have increased faulty recombination. Giventhe presence of translocations t(14; 14)(q11;q32) in T-prolymphocyticleukemias and T-cell tumors of non AT patients, our findingssuggest that VP16 could be considered an antineoplastic treatmentparticularly indicated in these patients.