Cyclin D1 and E2F-1 immunoreactivity in bone marrow biopsy specimens of multiple myeloma: relationship to proliferative activity, cytogenetic abnormalities and DNA ploidy.
Cyclin D1, encoded by the CCND1 gene, is immunohistochemically detectable in up to one-third of cases of multiple myeloma (MM). To examine the mechanism of cyclin D1 overexpression, we compared cyclin D1 immunoreactivity with the results of conventional cytogenetics to determine if the t(11;14)(q13;q32) or other abnormalities of 11q11-14 explained cyclin D1 overexpression. Karyotypic abnormalities were found in 45 out of 67 (67%) MM cases; the t(11;14) was present in seven cases (10%). Additional 11q11-14 abnormalities were not identified. The t(11;14) correlated with cyclin D1 upregulation in low to intermediately proliferative MM, but was not present in highly proliferative tumours (assessed using bromodeoxyuridine labelling index). Cyclin D1 indirectly activates the transcription factor E2F-1. In the bone marrow biopsy specimens of MM cases, E2F-1 was concurrently expressed with cyclin D1 (P = 0.001), indicating that cyclin D1 is functional. However, as neither E2F-1 nor cyclin D1 expression correlated with proliferative activity, the speculation that t(11;14) upregulates the CCND1 gene to induce higher proliferation and possibly more aggressive disease is not supported. We conclude that in low to intermediately proliferative MM cases, cyclin D1 is probably upregulated by t(11;14), but an alternative mechanism is more probable in highly proliferative MM.
University of Arkansas for Medical Sciences, Department of Pathology, Mail Slot 502, 4301 West Markham Street, Little Rock, AR 72205, USA. wilsoncarlas@exchange.uams.edu
C S
CS
Wilson
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Butch
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Lai
L J
LJ
Medeiros
J R
JR
Sawyer
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Barlogie
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McCourty
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Kelly
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Brynes
D000328:Adult; D000368:Aged; D001854:Bone Marrow Cells / Q000737:chemistry* / Q000473:pathology; D001973:Bromodeoxyuridine; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D019938:Cyclin D1 / Q000032:analysis* / Q000235:genetics; D020732:Cytogenetic Analysis; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005260:Female; D005434:Flow Cytometry; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000032:analysis*; D014178:Translocation, Genetic
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D019938:Cyclin D1; D001973:Bromodeoxyuridine