B细胞克隆作为慢性淋巴细胞白血病的早期标志物。
B-cell clones as early markers for chronic lymphocytic leukemia.
作者信息
Landgren Ola, Albitar Maher, Ma Wanlong, Abbasi Fatima, Hayes Richard B, Ghia Paolo, Marti Gerald E, Caporaso Neil E
机构信息
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
N Engl J Med. 2009 Feb 12;360(7):659-67. doi: 10.1056/NEJMoa0806122.
BACKGROUND
Otherwise healthy persons with a small number of B-cell clones circulating in the peripheral blood have been designated as having monoclonal B-cell lymphocytosis (MBL). Hospital-based series indicate an excess risk of progression from MBL to chronic lymphocytic leukemia (CLL). In this prospective cohort study, we tested the hypothesis that CLL is always preceded by MBL.
METHODS
Among 77,469 healthy adults who were enrolled in the nationwide, population-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 45 subjects in whom CLL was subsequently diagnosed (up to 6.4 years later) through the collection of a peripheral-blood sample. Using six-color flow cytometry (with antibodies CD45, CD19, CD5, CD10, kappa, and lambda) and immunoglobulin heavy-chain gene rearrangement by reverse-transcriptase-polymerase-chain-reaction assay, we determined the association between MBL and subsequent CLL and characterized the immunoglobulin gene repertoire of the prediagnostic B-cell clones.
RESULTS
On the basis of either flow-cytometric or molecular analysis, 44 of 45 patients with CLL (98%; 95% confidence interval [CI], 88 to 100) had a prediagnostic B-cell clone; in 41 patients (91%; 95% CI, 79 to 98), the presence of the B-cell clone was confirmed by both methods. The presence of immunoglobulin heavy-chain variable (IGHV) genes was determined in 35 of 45 prediagnostic clones (78%). Of these clones, 16 (46%) were IGHV3 subgroup genes (including 6 [17%] IGHV3-23 genes) and 9 (26%) were IGHV4 subgroup genes (including 4 [11%] IGHV4-34 genes). Furthermore, 27 of 35 of the IGHV sequences (77%) had mutations, with similar distributions after stratification either below or above the median time between the collection of the prediagnostic blood sample and the subsequent CLL diagnosis.
CONCLUSIONS
In peripheral blood obtained up to 77 months before a CLL diagnosis, prediagnostic B-cell clones were present in 44 of 45 patients with CLL.
背景
外周血中循环有少量B细胞克隆的健康个体被认定为患有单克隆B淋巴细胞增多症（MBL）。基于医院的系列研究表明，MBL进展为慢性淋巴细胞白血病（CLL）的风险增加。在这项前瞻性队列研究中，我们检验了CLL总是由MBL发展而来的假设。
方法
在参与全国性、基于人群的前列腺、肺、结肠直肠和卵巢（PLCO）癌症筛查试验的77469名健康成年人中，我们通过采集外周血样本，确定了45名随后被诊断为CLL的受试者（最长在6.4年后）。使用六色流式细胞术（采用抗CD45、CD19、CD5、CD10、κ和λ抗体）以及逆转录聚合酶链反应检测免疫球蛋白重链基因重排，我们确定了MBL与后续CLL之间的关联，并对诊断前B细胞克隆的免疫球蛋白基因库进行了特征分析。
结果
基于流式细胞术或分子分析，45例CLL患者中有44例（98%；95%置信区间[CI]，88%至100%）存在诊断前B细胞克隆；41例患者（91%；95%CI，79%至98%）通过两种方法均证实存在B细胞克隆。45个诊断前克隆中有35个（78%）确定了免疫球蛋白重链可变（IGHV）基因的存在。在这些克隆中，16个（46%）是IGHV3亚组基因（包括6个[17%]IGHV3-23基因），9个（26%）是IGHV4亚组基因（包括4个[11%]IGHV4-34基因）。此外，35个IGHV序列中有27个（77%）发生了突变，在诊断前血样采集与后续CLL诊断之间的中位时间上下分层后，分布相似。
结论
在CLL诊断前长达77个月采集的外周血中，45例CLL患者中有44例存在诊断前B细胞克隆。
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