Background: Canonical NF-κB signalling by p65 (RelA) confers chemo-resistance and poor survival in chronic lymphocytic leukaemia (CLL). The role of non-canonical NF-κB signalling (leading to RelB and p52 subunit activation) in CLL is less understood, but given its importance in other B-cell tumour types, we theorised that RelB and p52 may also contribute to the pathology of CLL. Methods: DNA binding activity of all five NF-kB subunits, p65, p50, RelB, p52, and c-Rel, was quantified using ELISA and correlated to ex vivo chemoresistance, CD40L-stimulated signalling (to mimic the lymph node microenvironment), and clinical data. Results: Importantly, we show for the first time that high basal levels of RelB DNA binding correlate with nuclear RelB protein expression and are associated with del(11q), ATM dysfunction, unmutated IGHV genes, and shorter survival. High levels of nuclear p65 are prevalent in del(17p) cases (including treatment-naïve patients) and also correlate with the outcome. CD40L-stimulation resulted in rapid RelB activation, phosphorylation and processing of p100, and subsequent CLL cell proliferation. Conclusions: These data highlight a role for RelB in driving CLL cell tumour growth in a subset of patients and therefore strategies designed to inhibit non-canonical NF-κB signalling represent a novel approach that will have therapeutic benefit in CLL.
背景：在慢性淋巴细胞白血病（CLL）中，p65（RelA）介导的经典NF-κB信号通路与化疗耐药及不良预后相关。非经典NF-κB信号通路（导致RelB和p52亚基激活）在CLL中的作用尚不明确，但鉴于其在其他B细胞肿瘤类型中的重要性，我们推测RelB和p52可能同样参与CLL的病理过程。方法：采用ELISA技术定量检测所有五种NF-κB亚基（p65、p50、RelB、p52和c-Rel）的DNA结合活性，并将其与外源性化疗耐药性、CD40L刺激信号（模拟淋巴结微环境）及临床数据进行关联分析。结果：重要的是，我们首次发现高基础水平的RelB DNA结合活性与核内RelB蛋白表达相关，并与del(11q)、ATM功能异常、未突变的IGHV基因及较短生存期存在关联。高水平的核p65在del(17p)病例（包括初治患者）中普遍存在，且同样与预后相关。CD40L刺激可快速激活RelB，促进p100磷酸化与加工，进而驱动CLL细胞增殖。结论：这些数据揭示了RelB在特定患者亚群中驱动CLL肿瘤生长的作用，因此针对非经典NF-κB信号通路的抑制策略将成为CLL治疗的新途径，具有重要临床价值。
肿瘤(癌症)患者之家