Siebolts Udo, Breuhahn Kai, Hennecke Andrea, Schultze Joachim L, Wickenhauser Claudia
Institute of Pathology, University of Cologne, Cologne, Germany.
Int J Cancer. 2009 Feb 1;124(3):600-7. doi: 10.1002/ijc.23985.
Polycythemia vera (PV) is a clonal hematopoietic stem cell disease characterized by a trilinear accumulation of blood cells that has been recently associated with a JAK2V617F point mutation. However, this molecular defect represents a rather late event in the disease progression, is not specific for this disease, and is not ascertained in all patients indicating that additional factors contribute to the specific phenotype of PV. Therefore, cDNA microarray analyses were performed on CD34+ peripheral blood stem cells (PBSC) with subsequent evaluation on mRNA and protein level of a larger cohort of PV patients. Microarray analyses revealed a significant dysregulation of 11 genes. KU86, a gene coding for a subunit of the DNA-dependent protein kinase (DNA-PK), displayed the strongest upregulation in all patients under study. This peculiarity was accompanied by downregulation of the catalytic DNA-PK subunit DNA-PKcs. Also Ku86 protein was upregulated and expressed in the vast majority of CD34+ PBSC nuclei while a weak nuclear expression was detected in only one blood donor. Differential expression of several genes, imbalance of the distinct subunits of DNA-PK, and particularly the strong upregulation of Ku86 protein, are new findings in PV CD34+ PBSC. These factors may contribute to the accumulation of chromosomal aberrations, accumulation of hematopoietic cells (especially of erythropoiesis), and prolongation of CD34+ PBSC life span observed in PV.
真性红细胞增多症（PV）是一种克隆性造血干细胞疾病，其特征为血细胞三系增生，最近发现它与JAK2V617F点突变有关。然而，这种分子缺陷在疾病进展过程中出现得较晚，并非PV所特有，且并非在所有患者中都能检测到，这表明还有其他因素导致了PV的特定表型。因此，我们对CD34 +外周血干细胞（PBSC）进行了cDNA微阵列分析，并随后在更多PV患者中对mRNA和蛋白质水平进行了评估。微阵列分析显示11个基因存在明显的失调。KU86是一种编码DNA依赖性蛋白激酶（DNA-PK）亚基的基因，在所研究的所有患者中上调最为明显。这种异常伴随着催化性DNA-PK亚基DNA-PKcs的下调。此外，Ku86蛋白上调并在绝大多数CD34 + PBSC细胞核中表达，而在仅一名献血者中检测到微弱的核表达。几个基因的差异表达、DNA-PK不同亚基的失衡，特别是Ku86蛋白的强烈上调，是PV CD34 + PBSC中的新发现。这些因素可能导致PV中观察到的染色体畸变积累、造血细胞（尤其是红细胞生成）积累以及CD34 + PBSC寿命延长。
