Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
Haematologica. 2010 Nov;95(11):1880-8. doi: 10.3324/haematol.2010.025734. Epub 2010 Aug 16.
Chronic lymphocytic leukemia has a variable clinical course. Genomic aberrations identify prognostic subgroups, pointing towards distinct underlying biological mechanisms that are poorly understood. In particular it remains unclear whether the prognostic subgroups of chronic lymphocytic leukemia are characterized by different levels of leukemogenic proteins.
Expression of 23 proteins involved in apoptosis, proliferation, DNA damage, and signaling or whose genes map to chromosomal regions known to be critical in chronic lymphocytic leukemia was quantified in 185 cytogenetically well characterized cases of chronic lymphocytic leukemia using immunoblotting. Cases were categorized hierarchically into deletion(17p), deletion(11q), trisomy 12, deletion(13q) as sole abnormality or normal karyotype. Statistical analysis was performed for expression differences between these subgroups. In addition, the expression levels of CDK4, P27 and P53 were quantified over the clinical course and compared to levels in immunopurified B cells from healthy individuals.
In subgroups with a good prognosis, differential expression was mainly seen for proteins that regulate apoptosis. In contrast, in cytogenetic subgroups with a worse prognosis, differential expression was mostly detected for proteins that control DNA damage and proliferation. Expression levels of CDK4, P27 and P53 were higher compared to those in B cells from healthy individuals and significantly correlated with increasing hierarchical risk. In addition, no significant longitudinal changes of expression levels of CDK4, P27 and P53 could be detected in chronic lymphocytic leukemia patients.
Differences in expression levels of apoptosis- and proliferation-controlling proteins define distinct prognostic subgroups of chronic lymphocytic leukemia and uncover a correlation of levels of CDK4, P27 and P53 proteins with higher hierarchical risk.
慢性淋巴细胞白血病具有多变的临床病程。基因组异常可确定预后亚组，指向尚未完全理解的不同潜在生物学机制。特别是，慢性淋巴细胞白血病的预后亚组是否具有不同水平的白血病蛋白仍不清楚。
使用免疫印迹法在 185 例细胞遗传学特征良好的慢性淋巴细胞白血病病例中定量检测了 23 种参与凋亡、增殖、DNA 损伤和信号传导的蛋白质或其基因位于染色体区域的表达，这些区域已知在慢性淋巴细胞白血病中至关重要。病例按层次分为缺失(17p)、缺失(11q)、三体 12、缺失(13q)为唯一异常或正常核型。对这些亚组之间的表达差异进行了统计分析。此外，还定量检测了 CDK4、P27 和 P53 的表达水平，并与来自健康个体的免疫纯化 B 细胞中的水平进行了比较。
在预后良好的亚组中，主要观察到调节凋亡的蛋白质的差异表达。相比之下，在预后较差的细胞遗传学亚组中，主要检测到控制 DNA 损伤和增殖的蛋白质的差异表达。与健康个体的 B 细胞相比，CDK4、P27 和 P53 的表达水平较高，并且与增加的分层风险显著相关。此外，在慢性淋巴细胞白血病患者中未检测到 CDK4、P27 和 P53 表达水平的明显纵向变化。
凋亡和增殖控制蛋白表达水平的差异定义了慢性淋巴细胞白血病的不同预后亚组，并揭示了 CDK4、P27 和 P53 蛋白水平与较高的分层风险的相关性。
