文章：

del(11q)慢性淋巴细胞白血病进展中BIRC3单等位基因与双等位基因缺失的生物学意义

Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression

原文发布日期：2021-07-09

DOI: 10.1038/s41408-021-00520-5

类型: Article

开放获取: 是

英文摘要：

BIRC3 is monoallelically deleted in up to 80% of chronic lymphocytic leukemia (CLL) cases harboring del(11q). In addition, truncating mutations in the remaining allele of this gene can lead to BIRC3 biallelic inactivation, which has been shown to be a marker for reduced survival in CLL. Nevertheless, the biological mechanisms by which these lesions could contribute to del(11q) CLL pathogenesis and progression are partially unexplored. We implemented the CRISPR/Cas9-editing system to generate isogenic CLL cell lines harboring del(11q) and/or BIRC3 mutations, modeling monoallelic and biallelic BIRC3 loss. Our results reveal that monoallelic BIRC3 deletion in del(11q) cells promotes non-canonical NF-κB signaling activation via RelB-p52 nuclear translocation, being these effects allelic dose-dependent and therefore further enhanced in del(11q) cells with biallelic BIRC3 loss. Moreover, we demonstrate ex vivo in primary cells that del(11q) cases including BIRC3 within their deleted region show evidence of non-canonical NF-κB activation which correlates with high BCL2 levels and enhanced sensitivity to venetoclax. Furthermore, our results show that BIRC3 mutations in del(11q) cells promote clonal advantage in vitro and accelerate leukemic progression in an in vivo xenograft model. Altogether, this work highlights the biological bases underlying disease progression of del(11q) CLL patients harboring BIRC3 deletion and mutation.
 

摘要翻译： 

BIRC3基因在高达80%携带11号染色体长臂缺失（del(11q)）的慢性淋巴细胞白血病（CLL）病例中呈现单等位基因缺失。此外，该基因剩余等位基因的截短突变可导致BIRC3双等位基因失活，研究证实这种失活是CLL患者生存期缩短的标志物。然而，这些基因损伤影响del(11q) CLL发病机制与疾病进展的具体生物学机制尚未被完全阐明。我们运用CRISPR/Cas9基因编辑系统构建了携带del(11q）和/或BIRC3突变的同基因型CLL细胞系，模拟BIRC3单等位及双等位基因缺失状态。研究结果显示，在del(11q)细胞中单等位BIRC3缺失可通过RelB-p52核转位激活非经典NF-κB信号通路，且该效应具有等位基因剂量依赖性——在同时存在双等位BIRC3缺失的del(11q)细胞中进一步增强。此外，我们在原代细胞离体实验中发现，缺失区域包含BIRC3的del(11q)病例存在非经典NF-κB通路激活证据，该激活状态与高BCL2蛋白水平及对venetoclax药物的敏感性增强相关。进一步研究显示，del(11q)细胞中的BIRC3突变在体外可促进克隆优势，并在体内异种移植模型中加速白血病进展。综上，本研究揭示了携带BIRC3缺失与突变的del(11q) CLL患者疾病进展的生物学基础。

原文链接：

Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression