Chemosensitivity of B cell chronic lymphocytic leukemia and correlated expression of proteins regulating apoptosis, cell cycle and DNA repair

B cell chronic lymphocytic leukemia (B-CLL) cannot be cured with convention al chemotherapy, This clinical enigma appears to be at least partially due to the fact that B-CLL cells are resistant to programmed cell death (apopto sis) and that they are arrested in G0/G1 phase of the cell cycle. The reaso ns for the dysregulation of these two key cellular events in B-CLL are uncl ear. The present study aimed at determining correlations between the expres sion levels of proteins regulating apoptosis, cell cycle and DNA repair in B-CLL cells and normal B cells. In addition, the differential sensitivity o f B-CLL cells to drug-induced apoptosis was quantified. We show that in B-C LL cells levels of the death-suppressor Bcl-2 correlated positively with th ose of the pro-apoptotic protein Bar and of the cyclin-dependent kinase (cd k) inhibitor p27(Kip1). I, B-CLL cells levels of the anti-apoptotic Bcl-x(L ) showed a positive correlation with levels of the 80 kDa regulatory compon ent (Ku80) of the DNA-dependent protein kinase that is involved in DNA doub le-stranded break repair. These correlations were not detected in normal B cells. The sensitivity of leukemic cells to FLUD but not to ADM, CPM or to DEX was reduced in pre-treated patients. These data support the hypothesis that in B-CLL cells death-modulators and molecules modulating cell cycle an d DNA repair are regulated in a coordinated manner.