bcl-2 expression in plasma cells from neoplastic gammopathies and reactive plasmacytosis: a comparative study

Abstract

BACKGROUND AND OBJECTIVE: bcl-2 oncoprotein plays a major physiological role in hemopoietic and non-hemopoietic cells by preventing apoptosis (programmed cell death). Disregulation of this process may be important in oncogenesis and the response to treatment of patients with different hematological malignancies. We have investigated the levels of bcl-2 expression in plasma cells from patients with reactive plasmacytosis (RP), monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma (MM), correlating the bcl-2 expression and clinico-biological features in MM patients. DESIGN AND METHODS: The percentage of bcl-2 (+) plasma cells and levels of bcl-2 protein expression were investigated in 73 patients at diagnosis. Immunofluorescence and immunoenzymatic methods were applied using McAb against bcl-2 protein, and the intensity of protein expression was assessed by both the mean channel fluorescence intensity (MFI) and semiquantitative methods. To evaluate the intensity of bcl-2 expression in proliferating plasma cells, sequential double immunoenzymatic staining with McAb Ki-67 and bcl-2 was applied in 10 patients with MM. Correlations between bcl-2 expression and the clinico-biological features in MM patients were also studied. RESULTS: The proportion of bcl-2 (+) plasma cells was significantly higher in MGUS and MM than in RP (p < 0.001). The intensity of bcl-2 expression in plasma cells (assessed by MFI) was significantly different between all groups studied (p < 0.0001). RP showed lower expression than MGUS and MM patients. MM stage III patients demonstrated higher bcl-2 expression values than MGUS (p < 0.01). According to the proportion of plasma cells expressing Ki-67, patients with a proliferative index (Ki-67+) > 4% showed lower bcl-2 expression than patients with proliferative index < 4% (p < 0.05). Immunocytochemistry showed that plasma cells from RP had a lower intensity of bcl-2 expression than MM (p < 0.001), and double immunostaining Ki-67/bcl-2 demonstrated that the majority of proliferating plasma cells had weak bcl-2 expression. There was no correlation between bcl-2 expression and clinico-biological parameters, response to therapy or overall survival in MM patients. INTERPRETATION AND CONCLUSIONS: Globally, the number of bcl-2 (+) plasma cells and the intensity of protein expression in neoplastic gammopathies are significantly higher than in reactive plasmacytosis and bcl-2 levels tend to increase with disease stage. bcl-2 may be relevant to the pathogenesis of malignant gammopathies, prolonging the survival of plasma cells by preventing apoptosis and increasing the chance of acquiring additional gene defects. bcl-2 expression could also contribute to the resistance to chemotherapy observed in MM disease.