Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, Novara, Italy.
Blood. 2013 Jun 13;121(24):4902-5. doi: 10.1182/blood-2013-02-486209. Epub 2013 May 1.
Genetic lesions and B-cell receptor (BCR) signaling are both oncogenic drivers in chronic lymphocytic leukemia (CLL). However, scant data are available on preferential associations between specific genetic alterations and stereotyped BCR subsets. By analyzing 1419 cases, 2 CLL subsets (2 and 8) harboring stereotyped BCR are enriched in specific molecular alterations influencing disease course. SF3B1 mutations are the genetic hallmark of IGHV3-21-CLL belonging to subset 2 (52%) but are evenly represented in nonstereotyped IGHV3-21-CLL. Trisomy 12 (87%) and NOTCH1 mutations (62%) characterize IGHV4-39-CLL belonging to subset 8 but occur with the expected frequency in IGHV4-39-CLL with heterogeneous BCR. Clinically, co-occurrence of SF3B1 mutations and subset 2 BCR configuration prompts disease progression in IGHV3-21-CLL, whereas cooperation between NOTCH1 mutations, +12, and subset 8 BCR configuration invariably primes CLL transformation into Richter syndrome. These findings provide a proof of concept that specific stereotyped BCR may promote or select molecular lesions influencing outcome.
遗传损伤和 B 细胞受体 (BCR) 信号转导在慢性淋巴细胞白血病 (CLL) 中都是致癌驱动因素。然而，关于特定遗传改变与定型 BCR 亚群之间的优先关联的数据很少。通过分析 1419 例病例，发现 2 个含有定型 BCR 的 CLL 亚群（2 型和 8 型）中富集了影响疾病进程的特定分子改变。SF3B1 突变是属于 2 型亚群的 IGHV3-21-CLL 的遗传标志（占 52%），但在非定型 IGHV3-21-CLL 中也均匀分布。12 号三体（87%）和 NOTCH1 突变（62%）是属于 8 型亚群的 IGHV4-39-CLL 的特征，但在具有异质性 BCR 的 IGHV4-39-CLL 中以预期的频率发生。临床上，SF3B1 突变和 2 型 BCR 构型的共存提示 IGHV3-21-CLL 疾病进展，而 NOTCH1 突变、+12 和 8 型 BCR 构型的合作则始终促使 CLL 转化为 Richter 综合征。这些发现为特定定型 BCR 可能促进或选择影响结局的分子损伤提供了概念验证。
