Cell cycle regulatory protein expression in fresh acute myeloid leukemia cells and after drug exposure

Characteristics of treatment-induced cell cycle arrest are important for in vitro and in vivo sensitivity of acute myeloid leukemia (AML) cells to cyt otoxic drugs. We analyzed the expression of the major G1 cell cycle regulat ors (p21(Cip1) p27(Kip1), cyclins D, cyclin E and pRb) in 41 fresh AML cell samples. The level of p27 expression was the only factor correlated with t he response to chemotherapy, a high level of p27 expression being predictiv e of complete remission. There was a close relation between expression of p Rb, cyclin D2 and FAB subtype, illustrated by the absence of both proteins in most samples having a monocytic component (M4, M5). We also assessed the expressions of pRb, cyclin E, p21 and p27 and the activity of cdk2, the ma jor regulator of S-phase entry, after exposure to cytosine-arabinoside (Ara C) and daunorubicin (DNR), and found these proteins could characterize time - and dose-dependent cellular response to each drug. We observed hyperphosp horylated pRb, increased levels of cyclin E and a high cdk2 activity, but n o p21 induction, in AML cells exposed to 10(-6) M AraC. After exposure to 1 0(-5) M AraC, corresponding to the serum concentration reached in high-dose AraC regimens (HDAraC), a strong p21 induction was observed, associated wi th similarly overexpressed cyclin E and even higher cdk2 activity than afte r 10(-6) M AraC, while apoptosis was significantly increased. These data su ggest that cdk2 activity is likely to play a role in AraC-induced apoptosis in AML cells. This mechanism may account for high efficacy of HDAraC in ce lls showing little sensitivity to conventional AraC doses.