Ciardullo Carmela, Szoltysek Katarzyna, Zhou Peixun, Pietrowska Monika, Marczak Lukasz, Willmore Elaine, Enshaei Amir, Walaszczyk Anna, Ho Jia Yee, Rand Vikki, Marshall Scott, Hall Andrew G, Harrison Christine J, Soundararajan Meera, Eswaran Jeyanthy
Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK.
Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
Cancers (Basel). 2021 Dec 21;14(1):23. doi: 10.3390/cancers14010023.
Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a highly variable clinical outcome. There are well-established CLL prognostic biomarkers that have transformed treatment and improved the understanding of CLL biology. Here, we have studied the clinical significance of two crucial B cell regulators, BACH2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) and BCL6 (B-cell CLL/lymphoma 6), in a cohort of 102 CLL patients and determined the protein interaction networks that they participate in using MEC-1 CLL cells. We observed that CLL patients expressing low levels of and RNA had significantly shorter overall survival (OS) than high - and -expressing cases. Notably, their low expression specifically decreased the OS of immunoglobulin heavy chain variable region-mutated (IGHV-M) CLL patients, as well as those with 11q and 13q deletions. Similar to the RNA data, a low BACH2 protein expression was associated with a significantly shorter OS than a high expression. There was no direct interaction observed between BACH2 and BCL6 in MEC-1 CLL cells, but they shared protein networks that included fifty different proteins. Interestingly, a prognostic index (PI) model that we generated, using integrative risk score values of RNA expression, age, and 17p deletion status, predicted patient outcomes in our cohort. Taken together, these data have shown for the first time a possible prognostic role for in CLL and have revealed protein interaction networks shared by BCL6 and BACH2, indicating a significant role for BACH2 and BCL6 in key cellular processes, including ubiquitination mediated B-cell receptor functions, nucleic acid metabolism, protein degradation, and homeostasis in CLL biology.
慢性淋巴细胞白血病（CLL）是一种异质性疾病，临床结局差异很大。已有成熟的CLL预后生物标志物，这些标志物改变了治疗方式并增进了对CLL生物学的理解。在此，我们研究了两种关键的B细胞调节因子BACH2（BTB和CNC同源物1，碱性亮氨酸拉链转录因子2）和BCL6（B细胞CLL/淋巴瘤6）在102例CLL患者队列中的临床意义，并使用MEC-1 CLL细胞确定了它们参与的蛋白质相互作用网络。我们观察到，与高表达BACH2和BCL6 RNA的患者相比，低表达的CLL患者总生存期（OS）显著缩短。值得注意的是，它们的低表达尤其降低了免疫球蛋白重链可变区突变（IGHV-M）的CLL患者以及伴有11q和13q缺失患者的OS。与RNA数据相似，BACH2蛋白低表达与高表达相比，OS显著缩短。在MEC-1 CLL细胞中未观察到BACH2与BCL6之间有直接相互作用，但它们共享包含50种不同蛋白质的蛋白质网络。有趣的是，我们使用BACH2 RNA表达、年龄和17p缺失状态的综合风险评分值生成的预后指数（PI）模型可预测我们队列中患者的预后。综上所述，这些数据首次表明BACH2在CLL中可能具有预后作用，并揭示了BCL6和BACH2共享的蛋白质相互作用网络，表明BACH2和BCL6在关键细胞过程中具有重要作用，包括泛素化介导的B细胞受体功能、核酸代谢、蛋白质降解以及CLL生物学中的稳态。
