Mansouri Larry, Sutton Lesley-Ann, Ljungström Viktor, Bondza Sina, Arngården Linda, Bhoi Sujata, Larsson Jimmy, Cortese Diego, Kalushkova Antonia, Plevova Karla, Young Emma, Gunnarsson Rebeqa, Falk-Sörqvist Elin, Lönn Peter, Muggen Alice F, Yan Xiao-Jie, Sander Birgitta, Enblad Gunilla, Smedby Karin E, Juliusson Gunnar, Belessi Chrysoula, Rung Johan, Chiorazzi Nicholas, Strefford Jonathan C, Langerak Anton W, Pospisilova Sarka, Davi Frederic, Hellström Mats, Jernberg-Wiklund Helena, Ghia Paolo, Söderberg Ola, Stamatopoulos Kostas, Nilsson Mats, Rosenquist Richard
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
Central European Institute of Technology, Masaryk University and University Hospital Brno, 601 77 Brno, Czech Republic.
J Exp Med. 2015 Jun 1;212(6):833-43. doi: 10.1084/jem.20142009. Epub 2015 May 18.
NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.
核因子κB（NF-κB）在慢性淋巴细胞白血病（CLL）中持续激活；然而，其中涉及的分子机制仍 largely 未知。因此，我们在一个总计 315 例的 CLL 发现和验证队列中，对 NF-κB 通路内的 18 个核心复合体基因进行了靶向深度测序。最常发生突变的基因是 NFKBIE（21/315 例；7%），它编码 IκBε，IκBε 是正常 B 细胞中 NF-κB 的负调节因子。引人注目的是，这些病例中有 13 例携带相同的 4 碱基移码缺失，导致产生截短蛋白。对另外 377 例 CLL 病例的筛查显示，NFKBIE 畸变在预后不良患者中占主导地位，并且与较差的预后相关。还观察到了微小亚克隆和/或克隆进化，因此可能将这一复发性事件与疾病进展联系起来。与野生型患者相比具有 NFKBIE 缺失的病例显示 IκBε 蛋白水平降低、p65 抑制作用减弱，同时 p65 的磷酸化和核转位增加。鉴于 B 细胞受体（BcR）信号在 CLL 病理生物学中的核心作用，值得注意的是，IκBε 缺失在具有独特定型 BcR 的侵袭性病例中富集，这可能导致了它们的预后不良，并导致对 BcR 抑制剂的反应改变。由于在其他几种 B 细胞淋巴瘤中也观察到了 NFKBIE 缺失，我们的研究结果提示了淋巴瘤发生过程中 NF-κB 失调的一种新的共同机制。
