p27KIP1 is abnormally expressed in Diffuse Large B-Cell Lymphomas and is associated with an adverse clinical outcome

Abstract

Cell cycle progression is regulated by the combined action of cyclins, cyclin-dependent kinases (CDKs), and CDK-inhibitors (CDKi), which are negative cell cycle regulators. p27 KIP1 is a CDKi key in cell cycle regulation, whose degradation is required for G1/S transition. In spite of the absence of p27 KIP1 expression in proliferating lymphocytes, some aggressive B-cell lymphomas have been reported to show an anomalous p27 KIP1 staining. We analysed p27 KIP1 expression in a series of Diffuse Large B-cell Lymphoma (DLBCL), correlating it with the proliferative index and clinical outcome, to characterize the implications of this anomalous staining in lymphomagenesis in greater depth. For the above mentioned purposes, an immunohistochemical technique in paraffin-embedded tissues was employed, using commercially available antibodies, in a series of 133 patients with known clinical outcomes. Statistical analysis was performed in order to ascertain which clinical and molecular variables may influence outcome, in terms of disease-free survival (DFS) and overall survival (OS). The relationships between p27 KIP1 and MIB-1 (Ki-67) were also tested. An abnormally high expression of p27 KIP1 was found in lymphomas of this type. The overall correlation between p27 KIP1 and MIB-1 showed there to be no significant relationship between these two parameters, this differing from observations in reactive lymphoid and other tissues. Analysis of the clinical relevance of these findings showed that a high level of p27 KIP1 expression in this type of tumour is an adverse prognostic marker, in both univariate and multivariate analysis. These results show that there is abnormal p27 KIP1 expression in DLBCL, with adverse clinical significance, suggesting that this anomalous p27 KIP1 protein may be rendered non-functional through interaction with other cell cycle regulator proteins. © 1999 Cancer Research Campaign

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

“…Group 3 is composed of simultaneous detection of low/null p27 expression, increased p53 expression, and decreased Rb or p16 expression (three alterations: 11 cases). lecular networks regulating the cell cycle in malignancies provides valuable information for the understanding of the impaired regulation of these networks and permits further insight into oncogenesis (11,15,17,19,23,24,26,29,34,36). This approach was adopted in the present study to analyze the expression of p27 in relation with components of the p53 and Rb1 growth control pathways and the status of proliferation in 80 cases of DLBCL.…”

Multiple cell cycle regulator alterations in Richter's transformation of chronic lymphocytic leukemia

“…In this regard, RS parallels the immunohistochemical pattern of p27 immunoreactivity exhibited by most histologically aggressive lymphomas. 42,43,46,47 Due to the lack of p27 Kip1 gene gross aberrations as determined by Southern blot analysis, the p27 protein loss in RS could be explained by a post-translational mechanism, like an enhanced ubiquitin proteosome-mediated degradation, as has been described in MCL. 46 Whether this finding is an epiphenomenon of the high proliferative rate of RS cells or represents a relevant event in histologic transformation is not clear.…”

Discovery of an oncogenic activity in p27Kip1that causes stem cell expansion and a multiple tumor phenotype

“…During the course of tumorigenesis, there evidently is a selective advantage to preserving partial p27 expression, thus harnessing its ability to provide a growth advantage to the neoplasm Morosetti et al 1995;Pietenpol et al 1995;Ponce-Castaneda et al 1995;Spirin et al 1996;Fero et al 1998). (4) Clinical studies investigating the subcellular localization of p27 in tumors suggest that while the loss of nuclear p27 is commonly observed, mislocalization of p27 to the cytoplasm of tumor cells is correlated with high tumor grade and poor prognosis (Nakasu et al 1999;Saez et al 1999;Sanchez-Beato et al 1999;Slingerland and Pagano 2000;Philipp-Staheli et al 2001;Kouvaraki et al 2002;Liang et al 2002;Besson et al 2004a;Rosen et al 2005;Qi et al 2006).…”

“…Indeed, some studies have indicated that p27 levels in tumors do not always correlate with proliferative index, and increasing evidence points to the importance of the subcellular localization of p27 in the control of its function, with cytoplasmic localization being a negative prognostic factor in certain instances (Singh et al 1998;Nakasu et al 1999;Saez et al 1999;Sanchez-Beato et al 1999;Slingerland and Pagano 2000;Philipp-Staheli et al 2001;Kouvaraki et al 2002;Liang et al 2002;Besson et al 2004a;Rosen et al 2005;Qi et al 2006). This possibility is supported by in vivo studies: p27 +/− mice are more susceptible to tumor development than p27 −/− animals in mammary and prostate tumor models, suggesting an active contribution of the remaining p27 allele (Muraoka et al 2002;Gao et al 2004).…”