EXPRESSION OF RETINOBLASTOMA GENE-PRODUCT (PRB) IN MANTLE CELL LYMPHOMAS - CORRELATION WITH CYCLIN D1 (PRADI CCND1) MESSENGER-RNA LEVELS AND PROLIFERATIVE ACTIVITY/

Mantle cell lymphomas (MCLs) are molecularly characterized by bcl-1 re arrrangement and constant cyclin DI (PRAD-1/CCND1) gene overexpression , Cyclin DI is a GI cyclin that participates in the control of the cel l cycle progression by interacting with the retinoblastoma gene produc t (pRb), Inactivation of the Rb tumor suppressor gene has been implica tion the development of different types of human tumors including some high grade non-Hodgkin's lymphomas. To determine the role of the reti noblastoma gene in the pathogenesis of MCLs and its possible interacti on with cyclin DI, pRb expression was examined in 23 MCLs including 17 typical and 6 blastic variants by immunohistochemistry and Western bl ot Rb gene structure was studied in 13 cases by Southern blot, Cytogen etic analysis was performed in 5 cases, The results were compared with the cyclin D1 mRNA levels examined by Northern analysis, and the prol iferative activity of the tumors was measured by Ki-67 growth fraction and flow cytometry. pRb was expressed in all MCLs. The expression var ied 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), Bl astic variants showed higher numbers of PRb-positive cells (mean, 23%) than the typical cases (10%; P < 0.005) by, immunohistochemistry and, concordantly, higher levels of expression by Western blot, In additio n, the blastic cases also had nit increased expression of the phosphor ylated protein, No alterations in Rb gene structure were observed by S outhern blot analysis, Cyclin D1 mRNA levels were independent of pRb e xpression and the proliferative activity of the tumors, These findings suggest that pRb in MCLs is normally regulated in relation to the pro liferative activity of the tumors, Cyclin DI overexpression may play a role its the maintenance of cell proliferation by overcoming the supp ressive growth control of pRb.