The NFKBIE gene, which encodes the NF-κB inhibitor IκBε, is mutated in 3–7% of patients with chronic lymphocytic leukemia (CLL). The most recurrent alteration is a 4-bp frameshift deletion associated with NF-κB activation in leukemic B cells and poor clinical outcome. To study the functional consequences of NFKBIE gene inactivation, both in vitro and in vivo, we engineered CLL B cells and CLL-prone mice to stably down-regulate NFKBIE expression and investigated its role in controlling NF-κB activity and disease expansion. We found that IκBε loss leads to NF-κB pathway activation and promotes both migration and proliferation of CLL cells in a dose-dependent manner. Importantly, NFKBIE inactivation was sufficient to induce a more rapid expansion of the CLL clone in lymphoid organs and contributed to the development of an aggressive disease with a shortened survival in both xenografts and genetically modified mice. IκBε deficiency was associated with an alteration of the MAPK pathway, also confirmed by RNA-sequencing in NFKBIE-mutated patient samples, and resistance to the BTK inhibitor ibrutinib. In summary, our work underscores the multimodal relevance of the NF-κB pathway in CLL and paves the way to translate these findings into novel therapeutic options.

编码 NF-κB 抑制剂 IκBε 的NFKBIE基因在 3-7% 的慢性淋巴细胞白血病 (CLL) 患者中发生突变。最常见的改变是与白血病 B 细胞中 NF-κB 激活和不良临床结果相关的 4 bp 移码缺失。为了在体外和体内研究NFKBIE基因失活的功能后果，我们设计了 CLL B 细胞和 CLL 易感小鼠，以稳定下调NFKBIE表达，并研究其在控制 NF-κB 活性和疾病扩展中的作用。我们发现 IκBε 丢失导致 NF-κB 通路激活，并以剂量​​依赖性方式促进 CLL 细胞的迁移和增殖。重要的是，NFKBIE失活足以诱导淋巴器官中 CLL 克隆更快地扩增，并导致异种移植和转基因小鼠的侵袭性疾病的发展，从而缩短生存期。 IκBε 缺陷与 MAPK 通路的改变以及对 BTK 抑制剂伊布替尼的耐药性相关，NFKBIE突变患者样本中的 RNA 测序也证实了这一点。总之，我们的工作强调了 NF-κB 通路在 CLL 中的多模式相关性，并为将这些发现转化为新的治疗方案铺平了道路。