Summary Apoptosis can be triggered by cytotoxic agents and radiation currently used in cancer treatment. However, the apoptotic response appears to vary between cell types (normal or transformed) and between types of malignancy. Thus, irradiation induces apoptosis in normal human lymphocytes but not in lymphocytes derived from a subset of chronic lymphocytic leukaemia (CLL). Moreover, in this subset, spontaneous apoptosis is inhibited by irradiation. Why irradiation does not allow the initiation of the apoptotic death pathway could be explained, at least in part, and in agreement with recent findings on experimental models, by the activation of the transcriptional factor NF-KB, which is able to inhibit apoptotic cell response. Low doses (at which no effect is observed with normal human lymphocytes) of the highly specific proteasome inhibitor lactacystin are sufficient to trigger apoptosis in these malignant cells. Proteasome inhibition by lactacystin prevents the nuclear translocation of both p50 and p65 NF-KB subunits and sensitizes these cells to apoptosis by tumour necrosis factor (TNF)-a treatment. As this subset of CLL is totally resistant to any treatment, proteasome inhibition by lactacystin provides a new therapeutic approach to be explored, considering the sensitivity of malignant CLL-derived lymphocytes to be quite different from that of normal human lymphocytes.

Summary. Ubiquitin-proteasome-dependent protein processing appears to be an essential component in the control of radiation-induced apoptosis in human lymphocytes. This control is altered in chronic lymphocytic leukaemia (CLL), compared to that of normal human lymphocytes which mainly showed high apoptotic values after irradiation, but in some cases no sensitivity was observed. Interestingly, lactacystin activated the apoptotic pathway in both radioresistant and sensitive CLL cells, at doses which had no effect in normal cells where significantly higher concentrations were required. Therefore the resistance of some CLL cells to apoptosis initiation by radiation does not correlate to observed increased sensitivity to lactacystin. The nuclear level of the transcription factor NF-kB or the cytoplasmic level of IkBa remained unaltered upon irradiation or lactacystin CLL cells treatment, suggesting that the activity of the other factors involved in apoptotic death control were altered through proteasomal inhibition. These results strongly suggest an essential role of the ubiquitin system in apoptotic cell death control in CLL lymphocytes. The inhibition of proteasome-ubiquitin-dependent processing could be a discriminatory apoptotic stimulus between normal versus malignant lymphocytes and therefore might potentially be of use in this specific human pathology.

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An analysis of R-banded PHA-stimulated lymphocytes from 13 patients with secondary acute non-lymphocytic leukemia (S-ANLL) following breast cancer or lymphoma, and treatment by alkylating agents and/or radiotherapy, is reported. We found that chromosomes 5, 7, 11 and 17 are over-involved in structural rearrangements. These anomalies are similar to those observed in the same categories of patients without S-ANLL, and after in vitro treatment of normal lymphocytes by the alkylating agent melphalan. These anomalies are thus likely to be induced by treatment, independently of S-ANLL. However, the same chromosomes (5, 7, 11 and 17) are recurrently deficient in leukemic S-ANLL clones. In spite of these similarities, it remains unlikely that the deficiencies observed in leukemic clones were directly induced at the time of treatment. Probably, treatment of primary cancers induces nonrandom mutations of recessive genes located on these chromosomes as also indicated by chromosomal lesions. Various rearrangements including deletions of the homologous normal counterparts may then occur, unmasking mutated recessive genes. The latter stage would be concomitant with the leukemogenic process.

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