Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Cancer Res. 2019 Jan 15;79(2):360-371. doi: 10.1158/0008-5472.CAN-18-0781. Epub 2018 Nov 29.
Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells driven by B-cell receptor (BCR) signaling and activated primarily in the lymph node. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib effectively inhibits BCR-dependent proliferation and survival signals and has emerged as a breakthrough therapy for CLL. However, complete remissions are uncommon and are achieved only after years of continuous therapy. We hypothesized that other signaling pathways that sustain CLL cell survival are only partially inhibited by ibrutinib. In normal B cells, Toll-like receptor (TLR) signaling cooperates with BCR signaling to activate prosurvival NF-κB. Here, we show that an experimentally validated gene signature of TLR activation is overexpressed in lymph node-resident CLL cells compared with cells in the blood. Consistent with TLR activation, we detected phosphorylation of NF-κB, STAT1, and STAT3 in lymph node-resident CLL cells and in cells stimulated with CpG oligonucleotides . CpG promoted IRAK1 degradation, secretion of IL10, and extended survival of CLL cells in culture. CpG-induced TLR signaling was significantly inhibited by both an IRAK1/4 inhibitor and ibrutinib. Although inhibition of TLR signaling was incomplete with either drug, the combination achieved superior results, including more effective inhibition of TLR-mediated survival signaling. Our data suggest an important role for TLR signaling in CLL pathogenesis and in sustaining the viability of CLL cells during ibrutinib therapy. The combination of ibrutinib with a TLR pathway inhibitor could provide superior antitumor activity and should be investigated in clinical studies. SIGNIFICANCE: CLL relies on the concomitant cooperation of B-cell receptor and Toll-like receptor signaling; inhibition of both pathways is superior to inhibition of either pathway alone. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/2/360/F1.large.jpg.
慢性淋巴细胞白血病（CLL）是一种成熟 B 细胞恶性肿瘤，由 B 细胞受体（BCR）信号驱动，主要在淋巴结中激活。布鲁顿酪氨酸激酶（BTK）抑制剂伊布替尼可有效抑制 BCR 依赖性增殖和存活信号，已成为 CLL 的突破性治疗方法。然而，完全缓解并不常见，只有经过多年的连续治疗才能实现。我们假设，其他维持 CLL 细胞存活的信号通路仅被伊布替尼部分抑制。在正常 B 细胞中，Toll 样受体（TLR）信号与 BCR 信号协同作用，激活促生存 NF-κB。在这里，我们显示与血液中的细胞相比，淋巴结驻留的 CLL 细胞中过度表达了经实验验证的 TLR 激活基因特征。与 TLR 激活一致，我们在淋巴结驻留的 CLL 细胞和用 CpG 寡核苷酸刺激的细胞中检测到 NF-κB、STAT1 和 STAT3 的磷酸化。CpG 促进 IRAK1 降解、IL10 分泌，并延长 CLL 细胞在培养中的存活。IRAK1/4 抑制剂和伊布替尼均可显著抑制 CpG 诱导的 TLR 信号。虽然两种药物对 TLR 信号的抑制都不完全，但联合使用可获得更好的效果，包括更有效地抑制 TLR 介导的存活信号。我们的数据表明 TLR 信号在 CLL 发病机制中以及在伊布替尼治疗期间维持 CLL 细胞的活力方面发挥着重要作用。伊布替尼与 TLR 途径抑制剂的联合应用可能提供更好的抗肿瘤活性，应在临床研究中进行探索。意义：CLL 依赖于 B 细胞受体和 Toll 样受体信号的协同合作；抑制这两个通路优于单独抑制任何一个通路。
