Pallasch Christian Philipp, Schulz Alexandra, Kutsch Nadine, Schwamb Janine, Hagist Susanne, Kashkar Hamid, Ultsch Alfred, Wickenhauser Claudia, Hallek Michael, Wendtner Clemens-Martin
Laboratory of Cellular Immunotherapy, Clinic I of Internal Medicine, University of Cologne, Cologne, Germany.
Blood. 2008 Nov 15;112(10):4213-9. doi: 10.1182/blood-2008-05-157255. Epub 2008 Aug 15.
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.
抗凋亡因子过表达或细胞外生存信号介导的对凋亡刺激的抗性被认为是慢性淋巴细胞白血病（CLL）中恶性B细胞积累的原因。通过对公开可用的微阵列数据集进行单位转换分析，TOSO被鉴定为CLL中过表达的候选基因。基于106例患者的CLL样本，使用定量实时聚合酶链反应（PCR），与健康供体B细胞相比，TOSO的相对表达（RE）升高至6.8（P = 0.004）。CLL中高水平的TOSO表达与高白细胞计数、晚期Binet分期、先前对化疗的需求以及未突变的IgV(H)状态相关。具有增殖活性的CD38(+) 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，发现与对照细胞相比，B细胞受体（BCR）刺激显著诱导TOSO表达（RE；8.25对4.86；P = 0.01）。相反，CD40L信号显著降低TOSO表达（RE，2.60；P = 0.01）。总之，我们表明抗凋亡因子TOSO与疾病进展相关，并在增殖性CD38(+) CLL亚群中增强。与未突变的IgV(H)的关联以及通过BCR对TOSO的特异性诱导均表明自身反应性BCR信号是CLL中凋亡抗性的关键介质。
