Expression of the cell-cycle-related proteins E2F-1, p53, mdm-2, p21waf-1, and Ki-67 in multiple myeloma: correlation with cyclin-D1 immunoreactivity.
Approximately 30% of multiple myelomas (MMs) express cyclin D1 when assessed using immunohistochemical techniques. Cyclin D1 expression correlates with greater tumor burden in MM, because cyclin D1-positive cases are more frequently associated with extensive bone marrow involvement, i.e., high pathologic stage, than are cyclin D1-negative cases. The mechanisms that explain this association are unknown. To explore other differences between cyclin D1-positive and cyclin D1-negative MMs, we assessed 59 MMs immunohistochemically for several G1 cell-cycle regulatory proteins, including cyclin D1, E2F-1, p53, mdm-2, and p21waf-1, using routinely fixed and processed, paraffin-embedded bone marrow specimens. Twenty MMs (34%) were cyclin D1 positive, and 39 (66%) were 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 p21waf-1 (12/20 vs. 7/39, P = .003). There was no significant difference in mdm-2 expression between these groups. We also assessed proliferation rate using an antibody specific for the Ki-67 antigen. A relatively high percentage (> 20%) of Ki-67-positive cells was found in cyclin D1-positive MMs compared with cyclin D1-negative MMs (13/20 vs. 3/39, P < 0.001). These results suggest that cyclin D1-positive MMs are more likely to possess additional derangements involving other G1 cell-cycle regulatory proteins. We speculate that these abnormalities might result in increased proliferation, thereby explaining the correlation between cyclin D1 expression and greater tumor burden.
Division of Pathology, City of Hope National Medical Center, Duarte, California, USA.
R
R
Lai
L J
LJ
Medeiros
C S
CS
Wilson
N C
NC
Sun
C
C
Koo
A
A
McCourty
R K
RK
Brynes
D001854:Bone Marrow Cells / Q000378:metabolism; D002352:Carrier Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2