CDK1 and cyclin A expression is linked to cell proliferation and associated with prognosis in non-Hodgkin's lymphomas

Cellular proliferation is regulated by several kinasic complexes associatin g cyclins and their catalytic subunits cyclin-dependent kinases (CDKs). In order to gain insight into the mechanisms underlying proliferation in non-H odgkin's lymphoma (NHL), we examined the expression of certain cell cycle r egulatory proteins normally expressed in lymphoid cells, cyclins A, B, D3 a nd E and cdk1, 2, 4, and 6. In 70 patients presenting a previously untreate d lymphoma, cyclins and CDKs were studied by Western blotting and quantifie d by densitometry. Flow cytometry study of DNA content was carried out for all patients in order to study cell proliferation and level of ploidy. The results were analysed according to the histological types, the immunologica l phenotypes of the lymphomas and the outcome of the patients. Cdk1 and cyclin A were correlated with the percentage of cells in S and S+G 2/M phases, and significantly different according to the grade of malignanc y, with the lowest expression in low-, and the highest in high-grade NHL ac cording to the Working Formulation. In B-NHLs, cdk1, cyclin A, as well as c dk2, cyclin D3 and E expression was higher in the aneuploid than in the eup loid group. Our results point to some particularities of cell cycle regulat ion in two lymphoma sub-types: 1) a low expression of cyclin D3 and cdk6 in mantle cell lymphomas and 2) a discrepancy between the high proliferative activity and the level of protein expression in Burkitt's lymphomas. CDK1 a nd cyclin A showed a significant prognostic value for achievement of comple te remission (Cdk 1) and for both disease free (cyclin A) and overall survi val (cyclin A and cdk1): low protein level was associated with the best pro gnosis in B-NHLs. Our results show that differential cell cycle regulating protein expression may be associated with different biological and clinical behaviour of NHLs and confirm the usefulness of the study of cell cycle regulation as a tool for understanding lymphoid malignancies.