Low expression of p27 protein combined with altered p53 and Rb/p16 expression status is associated with increased expression of cyclin A and cyclin B1 in diffuse large B-cell lymphomas

The expression of the cyclin-dependent kinase inhibitor (CDKI) p27 protein was investigated in relation to (1) the expression of the cell cycle regula tors p53, Rb and p16 and (2) the proliferation profile as determined by the expression of Ki67, cyclin A, and cyclin BI in 80 cases of de novo diffuse large B-cell lymphomas (DLBCL). P27 expression was low/null in large tumor cells in 58/80 cases and intermediate/high in 22/80 cases. Increased expre ssion of p53 protein was observed in 39/80 cases. Decreased expression of R b and p16 proteins was mutually exclusive and was observed in 5/80 and 14/8 0 cases, respectively. The analysis of the p27 expression status (low/null versus intermediate/high) with respect to the p53 and/or Rb/p16 expression status showed that low/null p27 expression was significantly correlated wit h increased p53 expression (P = .018) and showed a strong trend for correla tion with concurrent increased p53 expression and decreased Rb or p16 expre ssion (P = .050). These findings suggest a tendency for concurrent alterati ons of the cell cycle regulators p27, p53, and Rb or p16 in DLBCL, which mi ght result in impaired tumor growth control. Indeed, the analysis of the co mbined p27/p53/Rb/p16 expression status with respect to the proliferation p rofile showed that (1) three alterations in the combined p27/p53/Rb/p16 sta tus (i.e., low/null P27 expression, increased expression of p53, and decrea sed expression of Rb or p16) were significantly correlated with increased e xpression of cyclin B1 (P = .005) and (2) two or three alterations were sig nificantly correlated with increased expression of cyclin A (P = .014). The se findings suggest combined impairment of a complex cell-cycle control net work involving the CDK inhibitor p27, the P53 pathway, and the Rbl pathway, which exerts a cooperative effect resulting in enhanced tumor cell prolife ration.