Expression of retinoblastoma gene product (pRb) in mantle cell lymphomas. Correlation with cyclin D1 (PRAD1/CCND1) mRNA levels and proliferative activity.
Mantle cell lymphomas (MCLs) are molecularly characterized by bcl-1 rearrangement and constant cyclin D1 (PRAD-1/CCND1) gene overexpression. Cyclin D1 is a G1 cyclin that participates in the control of the cell cycle progression by interacting with the retinoblastoma gene product (pRb). Inactivation of the Rb tumor suppressor gene has been implicated in the development of different types of human tumors including some high grade non-Hodgkin's lymphomas. To determine the role of the retinoblastoma gene in the pathogenesis of MCLs and its possible interaction with cyclin D1, pRb expression was examined in 23 MCLs including 17 typical and 6 blastic variants by immunohistochemistry and Western blot. Rb gene structure was studied in 13 cases by Southern blot. Cytogenetic analysis was performed in 5 cases. The results were compared with the cyclin D1 mRNA levels examined by Northern analysis, and the proliferative activity of the tumors was measured by Ki-67 growth fraction and flow cytometry. pRb was expressed in all MCLs. The expression varied from case to case (mean, 14.1% of positive cells; range, 1.3 to 42%) with a significant correlation with the proliferative activity of the tumors (mitotic index r = 0.85; Ki-67 r = 0.7; S phase = 0.73). Blastic variants showed higher numbers of pRb-positive cells (mean, 29%) than the typical cases (10%; P < 0.005) by immunohistochemistry and, concordantly, higher levels of expression by Western blot. In addition, the blastic cases also had an increased expression of the phosphorylated protein. No alterations in Rb gene structure were observed by Southern blot analysis. Cyclin D1 mRNA levels were independent of pRb expression and the proliferative activity of the tumors. These findings suggest that pRb in MCLs is normally regulated in relation to the proliferative activity of the tumors. Cyclin D1 overexpression may play a role in the maintenance of cell proliferation by overcoming the suppressive growth control of pRb.
Jares
P
P
Department of Anatomic Pathology, Postgraduate School of Hematology Farreras Valenti, Hospital Clinic, University of Barcelona, Spain.
Campo
E
E
Pinyol
M
M
Bosch
F
F
Miquel
R
R
Fernandez
P L
PL
Sanchez-Beato
M
M
Soler
F
F
Perez-Losada
A
A
Nayach
I
I
Mallofré
C
C
Piris
M A
MA
Montserrat
E
E
Cardesa
A
A
D000368:Aged; D000369:Aged, 80 and over; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division / Q000502:physiology; D019938:Cyclin D1; D016213:Cyclins / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D016161:Genes, Retinoblastoma / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008228:Lymphoma, Non-Hodgkin / Q000737:chemistry* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015513:Oncogene Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis* / Q000235:genetics; D016160:Retinoblastoma Protein / Q000032:analysis* / Q000235:genetics
D016213:Cyclins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D019938:Cyclin D1