Delmer A, Ajchenbaum-Cymbalista F, Tang R, Ramond S, Faussat A M, Marie J P, Zittoun R
Laboratoire de Cinétique et Culture Cellulaires, Hôtel-Dieu, Paris, France.
Blood. 1995 May 15;85(10):2870-6.
Tumor progression in B-cell chronic lymphocytic leukemia (B-CLL) is thought to result from the gradual accumulation of small resting G0/G1 phase lymphoid cells rather than the proliferation of actively dividing cells. The recent identification of G1 cyclins that are likely to control both the progression through G0 and G1 phase and the G1/S transition prompted us to study the mRNA expression of D-type cyclins in the peripheral blood lymphocytes from 34 patients with B-CLL, 7 patients with lymphoplasmacytic lymphoma (LPL), and 2 patients with mantle cell lymphoma (MCL). Cyclin D2 mRNA was, on average, 5- to 10-fold overexpressed 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 mRNA was barely detectable. In situ hybridization with cyclin D2 digoxigenin-labeled mRNA probe showed that all the cells from a given sample were stained with approximately the same intensity. Cyclin D3 was never detected in any of the samples tested, whereas cyclin D1 was expressed in only the 3 cases (1 LPL and 2 MCL) bearing a t(11;14) translocation. A trisomy 12 was found in 4 of 19 (21%) B-CLL or LPL cases for which cytogenetic analysis was available. Although the cyclin D2 gene has been mapped to chromosome 12p13, there was no apparent correlation between trisomy 12 and the level of cyclin D2 expression. Cell cycle analysis by flow cytometry after staining with propidium iodide consistently showed that more than 96% of the cells were in G0/G1 phase, whatever 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 and LPL. Therefore, it led us to hypothesize, with the support of data from some transfection experiments previously reported in murine hematopoietic cell lines, that cyclin D2 might play a role in B-CLL pathogenesis, possibly by preventing cells from programmed cell death.
B细胞慢性淋巴细胞白血病（B-CLL）中的肿瘤进展被认为是由处于静止G0/G1期的小淋巴细胞逐渐积累所致，而非活跃分裂细胞的增殖。最近发现的G1期细胞周期蛋白可能控制细胞通过G0期和G1期的进程以及G1/S期转换，这促使我们研究34例B-CLL患者、7例淋巴浆细胞淋巴瘤（LPL）患者和2例套细胞淋巴瘤（MCL）患者外周血淋巴细胞中D型细胞周期蛋白的mRNA表达。与正常静止B淋巴细胞相比，在大多数研究样本中（B-CLL，29/34；LPL，7/7；MCL，0/2），细胞周期蛋白D2 mRNA平均过表达5至10倍，而在正常静止B淋巴细胞中几乎检测不到细胞周期蛋白D2 mRNA。用洋地黄毒苷标记的细胞周期蛋白D2 mRNA探针进行原位杂交显示，给定样本中的所有细胞染色强度大致相同。在所检测的任何样本中均未检测到细胞周期蛋白D3，而细胞周期蛋白D1仅在3例（1例LPL和2例MCL）携带t(11;14)易位的病例中表达。在19例（21%）可进行细胞遗传学分析的B-CLL或LPL病例中，有4例发现12号染色体三体。尽管细胞周期蛋白D2基因已定位到12号染色体p13区，但12号染色体三体与细胞周期蛋白D2表达水平之间无明显相关性。用碘化丙啶染色后通过流式细胞术进行细胞周期分析始终显示，无论细胞周期蛋白D2过表达程度如何，超过96%的细胞处于G0/G1期，且B-CLL中细胞周期蛋白D2过表达与细胞周期分布的任何改变均无关。在急性髓系白血病中未发现细胞周期蛋白D2的一致过表达。总之，发现细胞周期蛋白D2 mRNA过表达是B-CLL和LPL中几乎恒定的特征。因此，在先前在小鼠造血细胞系中报道的一些转染实验数据的支持下，我们推测细胞周期蛋白D2可能在B-CLL发病机制中起作用，可能是通过防止细胞程序性死亡。
