Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease.
Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease.
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DOI：
10.1182/blood-2008-05-157255
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发表时间：
2008-11
期刊：
影响因子：
20.3
通讯作者：
C. Pallasch;A. Schulz;N. Kutsch;Janine Schwamb;S. Hagist;H. Kashkar;A. Ultsch;C. Wickenhauser
中科院分区：
文献类型：
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作者：
C. Pallasch;A. Schulz;N. Kutsch;Janine Schwamb;S. Hagist;H. Kashkar;A. Ultsch;C. Wickenhauser
抗凋亡因子或细胞外生存信号的过度表达介导的对凋亡刺激的抵抗被认为是慢性淋巴细胞白血病（CLL）中恶性B细胞积聚的原因。TOSO被确定为CLL中过表达的候选基因，应用公开可用的微阵列数据集的单位转化测定。基于来自106名患者的CLL样本，使用定量实时聚合酶链反应（PCR; P = .004），与健康供体B细胞相比，TOSO被鉴定为表现出升高的相对表达（RE）6.8。CLL中TOSO高水平表达与高白细胞计数、晚期Binet分期、既往化疗需要和未突变IgV（H）状态相关。具有增殖活性的CD 38（+）CLL亚群显示TOSO表达增强。我们评估了异常TOSO表达的功能机制，并鉴定了与对照细胞相比，B细胞受体（BCR）刺激显著诱导的TOSO表达（RE; 8.25 vs 4.86; P = 0.01）。相反，CD 40 L信号显著降低TOSO表达（RE，2.60; P = .01）。总之，我们发现抗凋亡因子TOSO与疾病进展相关，并且在增殖性CD 38（+）CLL亚群中增强。与未突变的IgV（H）的关联和通过BCR特异性诱导TOSO表明自身反应性BCR信号传导是CLL中细胞凋亡抗性的关键介导物。
Resistance toward apoptotic stimuli mediated by overexpression of antiapoptotic factors or extracellular survival signals is considered to be responsible for accumulation of malignant B cells in chronic lymphocytic leukemia (CLL). TOSO was identified as overexpressed candidate gene in CLL, applying unit-transformation assays of publicly available microarray datasets. Based on CLL samples from 106 patients, TOSO was identified to exhibit elevated relative expression (RE) of 6.8 compared with healthy donor B cells using quantitative real-time polymerase chain reaction (PCR; P = .004). High levels of TOSO expression in CLL correlated with high leukocyte count, advanced Binet stage, previous need for chemotherapy, and unmutated IgV(H) status. CD38(+) CLL subsets harboring proliferative activity showed enhanced TOSO expression. We evaluated functional mechanisms of aberrant TOSO expression and identified TOSO expression significantly induced by B-cell receptor (BCR) stimulation compared with control cells (RE; 8.25 vs 4.86; P = .01). In contrast, CD40L signaling significantly reduced TOSO expression (RE, 2.60; P = .01). In summary, we show that the antiapoptotic factor TOSO is associated with progressive disease and enhanced in the proliferative CD38(+) CLL subset. Both association with unmutated IgV(H) and the specific induction of TOSO via the BCR suggest autoreactive BCR signaling as a key mediator of apoptosis resistance in CLL.