极光 A 和 B 激酶在骨髓来源的慢性淋巴细胞白血病细胞中上调，代表潜在的治疗靶点。
The Aurora A and B kinases are up-regulated in bone marrow-derived chronic lymphocytic leukemia cells and represent potential therapeutic targets.
机构信息
Hematology Division and Center for Cell-Based Therapy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
出版信息
Haematologica. 2012 Aug;97(8):1246-54. doi: 10.3324/haematol.2011.054668. Epub 2012 Feb 13.
BACKGROUND
The malignant B cells in chronic lymphocytic leukemia receive signals from the bone marrow and lymph node microenvironments which regulate their survival and proliferation. Characterization of these signals and the pathways that propagate them to the interior of the cell is important for the identification of novel potential targets for therapeutic intervention.
DESIGN AND METHODS
We compared the gene expression profiles of chronic lymphocytic leukemia B cells purified from bone marrow and peripheral blood to identify genes that are induced by the bone marrow microenvironment. Two of the differentially expressed genes were further studied in cell culture experiments and in an animal model to determine whether they could represent appropriate therapeutic targets in chronic lymphocytic leukemia.
RESULTS
Functional classification analysis revealed that the majority of differentially expressed genes belong to gene ontology categories related to cell cycle and mitosis. Significantly up-regulated genes in bone marrow-derived tumor cells included important cell cycle regulators, such as Aurora A and B, survivin and CDK6. Down-regulation of Aurora A and B by RNA interference inhibited proliferation of chronic lymphocytic leukemia-derived cell lines and induced low levels of apoptosis. A similar effect was observed with the Aurora kinase inhibitor VX-680 in primary chronic lymphocytic leukemia cells that were induced to proliferate by CpG-oligonucleotides and interleukin-2. Moreover, VX-680 significantly blocked leukemia growth in a mouse model of chronic lymphocytic leukemia.
CONCLUSIONS
Aurora A and B are up-regulated in proliferating chronic lymphocytic leukemia cells and represent potential therapeutic targets in this disease.
背景
慢性淋巴细胞白血病的恶性 B 细胞从骨髓和淋巴结微环境中接收信号，这些信号调节它们的存活和增殖。这些信号的特征及其向细胞内部传播的途径对于鉴定治疗干预的新潜在靶点非常重要。
设计与方法
我们比较了从骨髓和外周血中纯化的慢性淋巴细胞白血病 B 细胞的基因表达谱，以鉴定受骨髓微环境诱导的基因。进一步研究了两个差异表达的基因在细胞培养实验和动物模型中的作用，以确定它们是否可以作为慢性淋巴细胞白血病的适当治疗靶点。
结果
功能分类分析表明，大多数差异表达的基因属于与细胞周期和有丝分裂相关的基因本体类别。在骨髓源性肿瘤细胞中显著上调的基因包括重要的细胞周期调节剂，如 Aurora A 和 B、survivin 和 CDK6。RNA 干扰下调 Aurora A 和 B 抑制慢性淋巴细胞白血病衍生细胞系的增殖，并诱导低水平的细胞凋亡。用 Aurora 激酶抑制剂 VX-680 在 CpG-寡核苷酸和白细胞介素-2诱导增殖的原发性慢性淋巴细胞白血病细胞中也观察到类似的效果。此外，VX-680 显著阻断了慢性淋巴细胞白血病小鼠模型中的白血病生长。
结论
Aurora A 和 B 在增殖的慢性淋巴细胞白血病细胞中上调，代表该疾病的潜在治疗靶点。
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