Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hum Pathol. 2011 Dec;42(12):1989-2000. doi: 10.1016/j.humpath.2011.02.027. Epub 2011 Jul 5.
Chronic lymphocytic leukemia bone marrow is characterized by increased angiogenesis. However, the molecular mediators of neovascularization and the biologic significance of increased endothelial cell proliferation in chronic lymphocytic leukemia require further investigation. Because signal transducer and activator of transcription 3 is constitutively activated in chronic lymphocytic leukemia, we studied the role of signal transducer and activator of transcription 3 in modulating vascular endothelial growth factor expression and the effect of vascular endothelial cells on chronic lymphocytic leukemia cells. Using chromatin immunoprecipitation, we found that anti-signal transducer and activator of transcription 3 antibodies immunoprecipitated DNA of signal transducer and activator of transcription 3, vascular endothelial growth factor, and other signal transducer and activator of transcription 3-regulated genes. In addition, signal transducer and activator of transcription 3-short interfering RNA significantly reduced messenger RNA levels of vascular endothelial growth factor in chronic lymphocytic leukemia cells, suggesting that signal transducer and activator of transcription 3 induces vascular endothelial growth factor expression in chronic lymphocytic leukemia. Remarkably, bone marrow chronic lymphocytic leukemia cells expressed high levels of vascular endothelial growth factor, and high vascular endothelial growth factor levels were detected in the plasma of patients with untreated chronic lymphocytic leukemia and correlated with white blood cell count. Chronic lymphocytic leukemia bone marrow biopsies revealed increased microvascular density and attachment of chronic lymphocytic leukemia cells to endothelial cells. Coculture of chronic lymphocytic leukemia cells and human umbilical vein endothelial cells showed a similar attachment. Furthermore, coculture studies with human umbilical vein endothelial cells showed that human umbilical vein endothelial cells protected chronic lymphocytic leukemia cells from spontaneous apoptosis by direct cell-to-cell contact as assessed by flow cytometry using annexin V. Our data suggest that constitutively activated signal transducer and activator of transcription 3 induces vascular endothelial growth factor production by chronic lymphocytic leukemia cells and that chronic lymphocytic leukemia cells derive a survival advantage from endothelial cells via cell-to-cell contact.
慢性淋巴细胞白血病骨髓的特征是血管生成增加。然而，新生血管的分子介质和慢性淋巴细胞白血病中内皮细胞增殖的生物学意义需要进一步研究。由于信号转导和转录激活因子 3 在慢性淋巴细胞白血病中持续激活，我们研究了信号转导和转录激活因子 3 在调节血管内皮生长因子表达中的作用以及血管内皮细胞对慢性淋巴细胞白血病细胞的影响。通过染色质免疫沉淀，我们发现抗信号转导和转录激活因子 3 抗体可免疫沉淀信号转导和转录激活因子 3、血管内皮生长因子和其他信号转导和转录激活因子 3 调节基因的 DNA。此外，信号转导和转录激活因子 3 短发夹 RNA 显著降低了慢性淋巴细胞白血病细胞中血管内皮生长因子的信使 RNA 水平，表明信号转导和转录激活因子 3 诱导慢性淋巴细胞白血病中血管内皮生长因子的表达。值得注意的是，骨髓慢性淋巴细胞白血病细胞表达高水平的血管内皮生长因子，并且在未经治疗的慢性淋巴细胞白血病患者的血浆中检测到高水平的血管内皮生长因子，并且与白细胞计数相关。慢性淋巴细胞白血病骨髓活检显示微血管密度增加，并且慢性淋巴细胞白血病细胞附着在内皮细胞上。慢性淋巴细胞白血病细胞与人脐静脉内皮细胞的共培养显示出类似的附着。此外，用人脐静脉内皮细胞进行的共培养研究表明，人脐静脉内皮细胞通过直接细胞间接触保护慢性淋巴细胞白血病细胞免受自发性凋亡，如通过流式细胞术使用 Annexin V 评估。我们的数据表明，持续激活的信号转导和转录激活因子 3 诱导慢性淋巴细胞白血病细胞产生血管内皮生长因子，并且慢性淋巴细胞白血病细胞通过细胞间接触从内皮细胞获得生存优势。
