EXPRESSION OF THE CELL-CYCLE-RELATED PROTEINS E2F-1, P53, MDM-2, P21(WAF-1), AND KI-67 IN MULTIPLE-MYELOMA - CORRELATION WITH CYCLIN-D1 IMMUNOREACTIVITY

Approximately 30% of multiple myelomas (MMs) express cyclin D1 when as sessed using immunohistochemical techniques. Cyclin D1 expression corr elates with greater tumor burden in MM, because cyclin D1-positive cas es are more frequently associated with extensive bone marrow involveme nt, i.e., high pathologic stage, than are cyclin D1-negative cases. Th e mechanisms that explain this association are unknown. To explore oth er differences between cyclin D1-positive and cyclin D1-negative MMs, we assessed 59 MMs immunohistochemically for several G(1) cell-cycle r egulatory proteins, including cyclin D1, E2F-1, p53, mdm-2 and p21(waf -1),using routinely fixed and processed, paraffin-embedded bone marrow specimens. Twenty MMs (34%) were cyclin D1 positive, and 39 (66%) wer e cyclin D1 negative. Eighteen (90%) of 20 cyclin D1-positive MMs were Stage III, in contrast to 19 (49%) of 39 cyclin D1-negative MMs (P = .003). Cyclin D1-positive MMs were more likely to express E2F-1 (16/20 vs. 4/39, P < .001), p53 (11/20 vs. 10/39, P = .041), and p21(waf-1) (12/20 vs. 7/39, P = .003). There was no significant difference in mdm -2 expression between these groups. We also assessed proliferation rat e using an antibody specific for the Ki-67 antigen. A relatively high percentage (> 20%) of Ki-67-positive cells was found in cyclin D1-posi tive MMs compared with cyclin D1-negative MMs (13/20 vs. 3/39, P < 0.0 01). These results suggest that cyclin D1-positive MMs are more likely to possess additional derangements involving other G(1) cell-cycle re gulatory proteins. We speculate that these abnormalities might result in increased proliferation, thereby explaining the correlation between cyclin D1 expression and greater tumor burden.