OVEREXPRESSION OF CYCLIN D2 IN CHRONIC B-CELL MALIGNANCIES

Tumor progression in B-cell chronic lymphocytic leukemia (B-CLL) is th ought to result from the gradual accumulation of small resting G0/G1 p hase lymphoid cells rather than the proliferation of actively dividing cells. The recent identification of G1 cyclins that are likely to con trol both the progression through GO and G1 phase and the G1/S transit ion prompted us to study the mRNA expression of D-type cyclins in the peripheral blood lymphocytes from 34 patients with B-CLL, 7 patients w ith lymphoplasmacytic lymphoma (LPL), and 2 patients with mantle cell lymphoma (MCL). Cyclin D2 mRNA was, on average, 5- to 10-fold overexpr essed in most of the samples studied (B-CLL, 29/34; LPL, 7/7; MCL, 0/2 ) as compared with normal resting B lymphocytes, in which cyclin D2 mR NA was barely detectable. In situ hybridization with cyclin D2 digoxig enin-labeled mRNA probe showed that all the cells from a given sample were stained with approximately the same intensity. Cyclin D3 was neve r detected in any of the samples tested, whereas cyclin D1 was express ed in only the 3 cases (1 LPL and 2 MCL) bearing a t(11;14) translocat ion. A trisomy 12 was found in 4 of 19 (21%) B-CLL or LPL cases for wh ich cytogenetic analysis was available. Although the cyclin D2 gene ha s been mapped to chromosome 12p13, there was no apparent correlation b etween trisomy 12 and the level of cyclin D2 expression. Cell cycle an alysis by flow cytometry after staining with propidium iodide consiste ntly showed that more than 96% of the cells were in G0/G1 phase, whate ver the importance of cyclin D2 overexpression was, and that cyclin D2 overexpression in B-CLL was not associated with any modifications of the cell cycle repartition. No consistent overexpression of cyclin D2 was found in acute myeloid leukemias. In conclusion, overexpression of cyclin D2 mRNA was found to be an almost constant feature in B-CLL an d LPL. Therefore, it led us to hypothesize, with the support of data f rom some transfection experiments previously reported in murine hemato poietic cell lines, that cyclin D2 might play a role in B-CLL pathogen esis, possibly by preventing cells from programmed cell death. (C) 199 5 by The American Society of Hematology.