Anomalous high p27/KIP1 expression in a subset of aggressive B-cell lymphomas is associated with cyclin D3 overexpression. p27/KIP1 - Cyclin D3 colocalization in tumor cells

p27 cyclin-dependent kinase inhibitor downregulation is essential for trans ition to the S phase of the cell cycle. Thus, proliferating cells in reacti ve lymphoid tissue show no detectable p27 expression. Nevertheless, anomalo us high p27 expression has been shown to be present in a group of aggressiv e B-cell lymphomas with high proliferation index and adverse clinical outco me, This suggests that abnormally accumulated p27 protein has been rendered functionally inactive. We analyzed the causes of this anomalous presence o f p27 in a group of aggressive B-cell lymphomas, including 54 cases of diff use large B-cell lymphomas and 20 Burkitt's lymphomas. We simultaneously st udied them for p27, cyclin D3, cyclin D2, cyclin D1, and cyclin E expressio n, because it has been stated that high levels of expression of cyclin D1 o r E lead to increased p27 levels in some cell types. A statistically signif icant association between p27 and cyclin D3 expression was found for the gr oup as a whole. Additionally, when dividing the cases according to the leve l of expression of cyclin D3 by reactive germinal centers, it was observed that cases with stronger cyclin D3 expression also show higher p27 expressi on. The relationship between both proteins was also shown at a subcellular level by laser confocal studies, showing that in cases with high expression of both proteins there was a marked colocalization. Additional evidence in favor of p27 sequestration by cyclin D3 was provided by coimmunoprecipitat ion studies in a Burkitt's cell line (Raji) showing the existence of cyclin D3/p27 complexes and the absence of CDK2/p27 complexes. These results coul d support the hypothesis that there are cyclin D3/p27 complexes in a subset of aggressive B-cell lymphomas in which p27 lacks the inhibitory activity found when it is bound to cyclin E/CDK2 complexes. This interaction between both proteins could lead to an abnormal nuclear accumulation, detectable b y immunohistochemical techniques. (C) 1999 by The American Society of Hemat ology.