Bcl-2, Bax and p53 expression in B-CLL in relation to in vitro survival and clinical progression.
Our previous data have shown that isolated leukemic cells from progressive chronic lymphocytic leukemia (B-CLL) patients respond to growth stimulation in vitro and express high levels of p53, immunoreactive with the configuration-specific antibody PAb 240. We have now analyzed the in vitro survival of B-CLL cells in relation to Bcl-2, Bax alpha and p53 expression and compared this with the clinical progression of the disease. Leukemic cells from patients with progressive disease demonstrated higher in vitro survival, compared with non-progressive B-CLL and normal B cells. All cells were sensitive to treatment with a combination of glucocorticoid and cAMP. Bcl-2 protein levels were not related to clinical progression, as measured by flow cytometry. Competitive PCR showed that Bcl-2 mRNA was over-expressed in most of the B-CLL samples and that p53 mRNA expression was similar between B-CLL groups and normal values and thus not related to clinical progression. However, since Bax alpha expression was lower in progressive than in non-progressive patients, the Bcl-2/Bax alpha ratio at the mRNA level was significantly higher in the progressive group. Our data suggest that the Bcl-2/Bax alpha ratio is important for the regulation of B-CLL cell survival, that p53 over-expression in progressive B-CLL is the result of post-transcriptional modifications and that a directed PKA activation may potentiate the cytolytic effect of glucocorticoids in vivo.
Aguilar-Santelises
M
M
Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden.
Rottenberg
M E
ME
Lewin
N
N
Mellstedt
H
H
Jondal
M
M
D000368:Aged; D001483:Base Sequence; D002455:Cell Division; D002470:Cell Survival; D004249:DNA Damage; D017931:DNA Primers / Q000737:chemistry; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D015448:Leukemia, B-Cell / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D003907:Dexamethasone