División Patología Molecular, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Buenos Aires, Argentina.
Instituto Nacional de Câncer, Río de Janeiro, RJ, Brazil.
Ann Hematol. 2022 Feb;101(2):341-348. doi: 10.1007/s00277-021-04703-9. Epub 2021 Oct 28.
Chronic lymphocytic leukemia (CLL) is the most common mature B-cell neoplasm in the West. IGHV4-34 is one of the most frequently used genes in CLL patients, which usually display an indolent outcome. In this study, we explored the mutational profile of CLL patients expressing IGHV4-34 within different stereotypes and their association with prognostic factors and clinical outcome. A multi-institutional cohort of unselected 1444 CLL patients was analyzed by RT-PCR and bidirectional sequencing. Cytogenetics and molecular cytogenetics analyses were also performed. We identified 144 (10%) IGHV4-34 expressing cases, 119 mutated (M), 44 of them with stereotyped B-cell receptors. Subset #4 was the most frequent (56.8% of cases) followed by subsets #16 (13.6%), #29 (6.8%), and #201 (2.3%), with different distribution among countries. Analysis of somatic hypermutation profile showed significant differences among stereotyped subsets for G28>D/E, P45>S, E55>Q, and S64>I changes (p < 0.01) and high frequency of disruption of the glycosylation motif in the VH CDR2 region. All stereotyped IGHV4-34 cases showed normal karyotypes. Deletion 13q14 as a sole alteration was present in 42.8% of stereotyped cases with a different distribution among subsets. A shorter time to first treatment was found in non-stereotyped vs. stereotyped M-IGHV4-34 patients (p = 0.034). Our results add new information supporting the importance of recurrent amino acid changes at particular positions, contributing to refine the molecular characterization of South American CLL patients.
慢性淋巴细胞白血病（CLL）是西方最常见的成熟 B 细胞肿瘤。IGHV4-34 是 CLL 患者中最常用的基因之一，通常表现为惰性结果。在这项研究中，我们探索了在不同表型中表达 IGHV4-34 的 CLL 患者的突变谱及其与预后因素和临床结果的关系。通过 RT-PCR 和双向测序分析了一个多机构的未选择的 1444 例 CLL 患者队列。还进行了细胞遗传学和分子细胞遗传学分析。我们鉴定了 144 例（10%）表达 IGHV4-34 的病例，其中 119 例为突变型（M），其中 44 例为定型 B 细胞受体。亚型 #4 最为常见（56.8%的病例），其次是亚型 #16（13.6%）、#29（6.8%）和 #201（2.3%），不同国家的分布不同。体细胞超突变谱分析显示，定型亚组之间在 G28>D/E、P45>S、E55>Q 和 S64>I 变化方面存在显著差异（p<0.01），并且 VH CDR2 区域的糖基化基序高频中断。所有定型的 IGHV4-34 病例均显示正常核型。在 42.8%的定型病例中，除了 13q14 缺失外，还存在单独的改变，在不同的亚组中分布不同。非定型与定型 M-IGHV4-34 患者相比，首次治疗时间更短（p=0.034）。我们的结果提供了新的信息，支持特定位置的反复氨基酸变化的重要性，有助于完善南美 CLL 患者的分子特征。
