Chronic lymphocytic leukaemia (CLL) cells are strongly influenced by microenvironmental signals through the activation of distinct membrane receptors including the B-cell receptor and toll-like receptors (TLR). Recapitulating TLR stimulation in vitro by treating CLL cells with the TLR9 ligand CpG can induce metabolic activation and protection from apoptosis. We hypothesized that interfering with TLR signalling may be beneficial for treating CLL, and we tested in preclinical studies the effect of a specific interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitory small molecule on primary leukaemic cells isolated from the peripheral blood of patients. We observed that IRAK4, an upstream kinase of the TLR pathway, is expressed in patients with CLL, and lower IRAK4 mRNA levels associate with a better outcome. The specific IRAK4 inhibitor disrupted TLR signalling as assessed by reduction of the specific biomarkers NFKBIZ and interleukin-6 mRNAs, and restrained the protective effect of in vitro TLR stimulation on cell viability. To note, IRAK4 inhibitor induced p53 and triggered apoptosis. Co-treatment of CLL cells with increasing concentrations of IRAK4i and the Bruton tyrosine kinase inhibitor ibrutinib demonstrated a synergistic effect. Our results suggest that targetting IRAK4 may represent a novel approach in CLL and may be combined with other signalling inhibitors.

中文翻译：

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白介素-1受体相关的激酶4抑制剂中断toll样受体信号转导并使慢性淋巴细胞性白血病细胞对凋亡敏感。

慢性淋巴细胞白血病（CLL）细胞通过激活包括B细胞受体和toll样受体（TLR）在内的独特膜受体而受到微环境信号的强烈影响。通过用TLR9配体CpG处理CLL细胞在体外概括TLR刺激，可以诱导代谢激活和保护细胞凋亡。我们假设干扰TLR信号可能对治疗CLL有益，并且在临床前研究中测试了特定的白介素1受体相关激酶4（IRAK4）抑制性小分子对从患者外周血分离的原代白血病细胞的作用。我们观察到IRL4，TLR途径的上游激酶，在CLL患者中表达，并且较低的IRAK4 mRNA水平与较好的预后相关。通过减少特定生物标志物NFKBIZ和白细胞介素6 mRNA的评估，特异性IRAK4抑制剂破坏了TLR信号传导，并抑制了体外TLR刺激对细胞生存力的保护作用。注意，IRAK4抑制剂诱导p53并触发凋亡。用增加浓度的IRAK4i和Bruton酪氨酸激酶抑制剂依鲁替尼共同治疗CLL细胞表现出协同作用。我们的结果表明，靶向IRAK4可能代表CLL中的一种新方法，并且可能与其他信号抑制剂结合。用增加浓度的IRAK4i和Bruton酪氨酸激酶抑制剂ibrutinib共同处理CLL细胞表现出协同作用。我们的结果表明，靶向IRAK4可能代表CLL中的一种新方法，并且可能与其他信号抑制剂结合。用增加浓度的IRAK4i和Bruton酪氨酸激酶抑制剂ibrutinib共同处理CLL细胞表现出协同作用。我们的结果表明，靶向IRAK4可能代表CLL中的一种新方法，并且可能与其他信号抑制剂结合。