Divergent Expression of Cclin-Dependent Kinase Inhibitors (CKI) And p14ARF/p16β in Non-Hodgkin's Lymphomas and Chronic Lymphocytic Leukemia

Abstract

Chronic B-cell lymphocytic leukaemia (CLL) and low-grade B-cell Non Hodgkin's lymphomas (Lg-NHL) are characterized by slow accumulation of neoplastic cells arrested in the GO/Gl phase of the cell cycle. In contrast, proliferation rates are high in aggressive B-cell lymphomas (Hg-NHL). Divergent expression of cyclin-dependent kinase inhibitors (CKI) in the cell cycle may contribute to these differences. We analysed CLL as well as low and high grade B-cell NHL for expression of GI-specific and universal CKI by competitive RT-PCR and immun-ostaining. p16INK4Aexpression was low in all types of neoplasms. Highest pl4ARF/pl6β expression levels were found in normal lymphocytes. Expression of this CKI was significantly lower in CLL, but still higer in CLL than in the lymphomas (median 27 vs. 3 mRNA transcipts x 103, p = 0.0001). p14ARF/p16β immunostaining correlated with mRNA expression. Highest p21 mRNA levels were found in CLL, but three of four CLL with abundant p21 mRNA production were negative on immunostaining. High grade lymphomas showed markedly decreased p21 expression (3.9 in Hg-NHL vs. 12 in Lg-NHL and 29 in CLL; values expressed as mRNA transcipts x 103, p < 0.009). mRNA and protein expression of p27 was considerably higher in CLL than in the lymphomas. Differential CKI expression in various B-cell neoplasias may provide important biological markers, if not the molecular underpinning of their different cell cycle kinetics. Targeted interference with such genes governing cell cycle control in lymphoid neopla-sia may pave the way towards new treatment strategies.