Am J Hematol. 2014 Jan;89(1):74-82. doi: 10.1002/ajh.23591.
Chronic lymphocytic leukemia (CLL) with stereotyped B-cell receptor (BCR) belonging to subset #1 (IGHV1-5-7/ IGKV1-39) display a poor outcome. To characterize their genetic and genomic features and BCR function, we selected 20 subset #1 CLL from a series of 579 cases. Subset #1 CLL, all showing unmutated IGHV, were associated with the presence of del(11q) (50%) in comparison with unmutated CLL, unmutated stereotyped CLL other than subset #1 and with cases using the same IGHV genes but a heterogeneous VH CDR3 (non-subset #1 CLL). There were no distinctive features regarding CD38, ZAP-70, and TP53 disruption. NOTCH1, SF3B1, and BIRC3 were mutated in 15%, 0%, and 5% of cases, respectively, while BIRC3 was deleted in 22% of cases. Microarray unsupervised analysis on 80 unmutated/mutated/stereotyped/non-stereotyped CLL showed a tight clustering of subset #1 cases. Their genomic signature exhibited several differentially expressed transcripts involved in BCR signal transduction, apoptosis regulation, cell proliferation, and oxidative processes, regardless of del(11q). Accordingly, BCR ligation with anti-IgM revealed a significant higher proliferation of subset #1 versus unmutated non-subset #1 CLL, both at baseline and after 24–48 hr stimulation. Subset #1 CLL represent a paradigmatic example of the direct link between BCR structure, function, and patients prognosis.
慢性淋巴细胞白血病（CLL）伴定型 B 细胞受体（BCR）属于亚型 #1（IGHV1-5-7/IGKV1-39）的患者预后较差。为了研究其遗传和基因组特征及 BCR 功能，我们从 579 例患者中选择了 20 例亚型 #1 CLL。与未突变的 CLL、未突变的定型非亚型 #1 CLL和使用相同 IGHV 基因但 VH CDR3 不同的病例相比，所有表现为未突变 IGHV 的亚型 #1 CLL 均存在 del(11q)（50%）。在 CD38、ZAP-70 和 TP53 缺失方面，未发现具有特征性的特点。NOTCH1、SF3B1 和 BIRC3 的突变率分别为 15%、0%和 5%，而 BIRC3 的缺失率为 22%。对 80 例未突变/突变/定型/非定型 CLL 的微阵列无监督分析显示，亚型 #1 病例紧密聚集。其基因组特征显示，在 BCR 信号转导、凋亡调控、细胞增殖和氧化过程中存在几种差异表达的转录本，无论是否存在 del(11q)。因此，抗 IgM 交联 BCR 后，与未突变的非定型 #1 CLL 相比，亚型 #1 的增殖显著更高，无论是在基线还是在 24-48 小时刺激后。亚型 #1 CLL 代表了 BCR 结构、功能和患者预后之间直接联系的典型范例。
