Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
Clin Cancer Res. 2010 Jan 15;16(2):620-8. doi: 10.1158/1078-0432.CCR-09-1638. Epub 2010 Jan 12.
B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease whose outcome can be foreseen by investigating the mutational status of immunoglobulin heavy chain variable (IGHV) genes. Moreover, a different prognosis was reported for CLL expressing specific IGHV genes in the context or not of stereotyped B-cell receptors. Here we investigated novel associations between usage of specific IGHV genes and clinical features in CLL.
Among 1,426 CLL-specific IG-rearrangements, stereotyped B-cell receptor clusters never utilized the IGHV3-23 gene. Given this notion, this study was aimed at characterizing the IGHV3-23 gene in CLL, and identifying the properties of IGHV3-23-expressing CLL.
IGHV3-23 was the second most frequently used (134 of 1,426) and usually mutated (M; 109 of 134) IGHV gene in our CLL series. In the vast majority of M IGHV3-23 sequences, the configuration of the 13 amino acids involved in superantigen recognition was consistent with superantigen binding. Clinically, M IGHV3-23 CLL had shorter time-to-treatment than other M non-IGHV3-23 CLL, and multivariate analyses selected IGHV3-23 gene usage, Rai staging, and chromosomal abnormalities as independent prognosticators for M CLL. Compared with M non-IGHV3-23 CLL, the gene expression profile of M IGHV3-23 CLL was deprived in genes, including the growth/tumor suppressor genes PDCD4, TIA1, and RASSF5, whose downregulation is under control of miR-15a and miR-16-1. Accordingly, relatively higher levels of miR-15a and miR-16-1 were found in M IGHV3-23 compared with M non-IGHV3-23 CLL.
Altogether, expression of the IGHV3-23 gene characterizes a CLL subset with distinct clinical and biological features.
B 细胞慢性淋巴细胞白血病（CLL）是一种临床表现异质性很强的疾病，通过研究免疫球蛋白重链可变（IGHV）基因的突变状态，可以预测其预后。此外，在 CLL 中表达特定 IGHV 基因时，B 细胞受体的结构是否存在差异，其预后也存在差异。本研究旨在探讨 CLL 中特定 IGHV 基因的使用与临床特征之间的新关联。
在 1426 个 CLL 特异性 IG 重排中，没有一个定型 B 细胞受体簇使用 IGHV3-23 基因。基于这一概念，本研究旨在研究 CLL 中的 IGHV3-23 基因，并确定表达 IGHV3-23 的 CLL 的特性。
IGHV3-23 是我们 CLL 系列中第二常用（1426 个中的 134 个）和通常突变（M；134 个中的 109 个）的 IGHV 基因。在绝大多数 M IGHV3-23 序列中，涉及超抗原识别的 13 个氨基酸的构象与超抗原结合一致。临床上，M IGHV3-23 CLL 的治疗时间短于其他 M 非 IGHV3-23 CLL，多变量分析选择 IGHV3-23 基因使用、Rai 分期和染色体异常作为 M CLL 的独立预后因素。与 M 非 IGHV3-23 CLL 相比，M IGHV3-23 CLL 的基因表达谱缺乏 PDCD4、TIA1 和 RASSF5 等生长/肿瘤抑制基因，这些基因的下调受 miR-15a 和 miR-16-1 的调控。因此，在 M IGHV3-23 中发现相对较高水平的 miR-15a 和 miR-16-1 与 M 非 IGHV3-23 CLL 相比。
总之，IGHV3-23 基因的表达特征是一种具有独特临床和生物学特征的 CLL 亚群。
