The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia
The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia
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淋巴结微环境促进慢性淋巴细胞白血病的 B 细胞受体信号转导、NF-κB 激活和肿瘤增殖
DOI：
10.1182/blood-2010-05-284984
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发表时间：
2011-01-13
期刊：
影响因子：
20.3
通讯作者：
Wiestner, Adrian
中科院分区：
文献类型：
--
作者：
Herishanu, Yair;Perez-Galan, Patricia;Wiestner, Adrian
慢性淋巴细胞白血病（CLL）是一种成熟B淋巴细胞的不可治愈的恶性肿瘤，涉及血液、骨髓和次级淋巴器官如淋巴结（LN）。组织微环境在CLL发病机制中的作用是基于体外观察假设的，但其在体内的作用仍然不明确。为了阐明体内肿瘤-宿主相互作用的影响，我们从24名未经治疗的患者中纯化肿瘤细胞。同时从血液、骨髓和/或LN获得样品，并通过基因表达谱分析。我们确定LN是CLL发病机制的关键部位。LN中的CLL细胞显示基因签名上调，表明B细胞受体（BCR）和核因子-κ B活化。与抗原依赖性BCR信号传导和经典核因子-κ B激活一致，我们分别检测到SYK和I κ B α的磷酸化。BCR靶基因的表达在临床上更具侵袭性的CLL中更强，表明该亚型体内的BCR信号传导更有效。通过E2 F和c-MYC靶基因的表达定量并通过流式细胞术用Ki 67染色验证的肿瘤增殖在LN中最高，并且与临床疾病进展相关。这些数据确定了肿瘤微环境相互作用的破坏和BCR信号传导的抑制是CLL中有希望的治疗策略。本研究在http://clinicaltrials.gov上注册为NCT 00019370。（血。2011;117（2）：563-574）
Chronic lymphocytic leukemia (CLL), an incurable malignancy of mature B lymphocytes, involves blood, bone marrow, and secondary lymphoid organs such as the lymph nodes (LN). A role of the tissue microenvironment in the pathogenesis of CLL is hypothesized based on in vitro observations, but its contribution in vivo remains ill-defined. To elucidate the effects of tumor-host interactions in vivo, we purified tumor cells from 24 treatment-naive patients. Samples were obtained concurrently from blood, bone marrow, and/or LN and analyzed by gene expression profiling. We identified the LN as a key site in CLL pathogenesis. CLL cells in the LN showed up-regulation of gene signatures, indicating B-cell receptor (BCR) and nuclear factor-kappa B activation. Consistent with antigen-dependent BCR signaling and canonical nuclear factor-kappa B activation, we detected phosphorylation of SYK and I kappa B alpha, respectively. Expression of BCR target genes was stronger in clinically more aggressive CLL, indicating more effective BCR signaling in this subtype in vivo. Tumor proliferation, quantified by the expression of the E2F and c-MYC target genes and verified with Ki67 staining by flow cytometry, was highest in the LN and was correlated with clinical disease progression. These data identify the disruption of tumor microenvironment interactions and the inhibition of BCR signaling as promising therapeutic strategies in CLL. This study is registered at http://clinicaltrials.gov as NCT00019370. (Blood. 2011;117(2):563-574)