Chemosensitivity of B cell chronic lymphocytic leukemia and correlated expression of proteins regulating apoptosis, cell cycle and DNA repair
Chemosensitivity of B cell chronic lymphocytic leukemia and correlated expression of proteins regulating apoptosis, cell cycle and DNA repair
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DOI：
10.1038/sj.leu.2401636
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发表时间：
2000-01-01
期刊：
影响因子：
11.4
通讯作者：
Schriever, F
中科院分区：
文献类型：
--
作者：
Klein, A;Miera, O;Schriever, F
B细胞慢性淋巴细胞白血病(B-CLL)不能用常规化疗治愈，这一临床谜团至少部分是由于B-CLL细胞对细胞程序性死亡(细胞凋亡)具有抵抗力，并且它们被阻止在细胞周期的G0/G1期。B-CLL中这两个关键细胞事件调节失调的原因尚不清楚。本研究旨在确定调控细胞凋亡、细胞周期和DNA修复的蛋白质在B-CLL细胞和正常B细胞中的表达水平之间的相关性。此外，还量化了B-CLL细胞对药物诱导的细胞凋亡的不同敏感性。我们发现，在B-CLL细胞中，死亡抑制基因Bcl2的表达水平与促凋亡蛋白Bar和细胞周期蛋白依赖性激酶(CDK)抑制物p27(Kip1)的表达水平呈正相关。I、B-CLL细胞中抗凋亡蛋白Bclx(L)的表达水平与参与DNA双链断裂修复的DNA依赖性蛋白激酶80 kDa调节成分(Ku80)的表达水平呈正相关。这些相关性在正常B细胞中未被检测到。治疗前白血病细胞对Flud的敏感性降低，但对ADM、CPM和DEX的敏感性不降低。这些数据支持这样一种假设，即在B-CLL细胞中，调节细胞周期和DNA修复的死亡调节剂和分子是以一种协调的方式调节的。
B cell chronic lymphocytic leukemia (B-CLL) cannot be cured with conventional chemotherapy, This clinical enigma appears to be at least partially due to the fact that B-CLL cells are resistant to programmed cell death (apoptosis) and that they are arrested in G0/G1 phase of the cell cycle. The reasons for the dysregulation of these two key cellular events in B-CLL are unclear. The present study aimed at determining correlations between the expression levels of proteins regulating apoptosis, cell cycle and DNA repair in B-CLL cells and normal B cells. In addition, the differential sensitivity of B-CLL cells to drug-induced apoptosis was quantified. We show that in B-CLL cells levels of the death-suppressor Bcl-2 correlated positively with those of the pro-apoptotic protein Bar and of the cyclin-dependent kinase (cdk) inhibitor p27(Kip1). I, B-CLL cells levels of the anti-apoptotic Bcl-x(L) showed a positive correlation with levels of the 80 kDa regulatory component (Ku80) of the DNA-dependent protein kinase that is involved in DNA double-stranded break repair. These correlations were not detected in normal B cells. The sensitivity of leukemic cells to FLUD but not to ADM, CPM or to DEX was reduced in pre-treated patients. These data support the hypothesis that in B-CLL cells death-modulators and molecules modulating cell cycle and DNA repair are regulated in a coordinated manner.