成人T细胞白血病/淋巴瘤（ATL）至今无法治愈。NF-κB和干扰素调节因子4（IRF4）信号通路是ATL进展的关键存活通路之一。TGF-β活化激酶1（TAK1），一种IκB激酶活化激酶，触发NF-κB的激活。酚酞酸内酯类衍生物LL-Z1640-2是TAK1/细胞外信号调节激酶2（ERK2）的有效、不可逆抑制剂。本研究旨在考察LL-Z1640-2对ATL的治疗效果。LL-Z1640-2有效抑制ATL细胞的体内生长。它在体外诱导细胞凋亡并抑制ATL细胞p65/RelA的核转位。IRF4敲低强烈诱导ATL细胞死亡同时下调MYC。LL-Z1640-2以及NF-κB抑制剂BAY11-7082降低了IRF4和MYC的蛋白和mRNA水平，表明抑制了NF-κB-IRF4-MYC轴。LL-Z1640-2处理还减轻了p38 MAPK的磷酸化以及CC趋化因子受体4的表达。此外，在IL-2的存在下，静止状态的LL-Z1640-2对IL-2敏感的ATL细胞的细胞毒活性得到了增强。因此，LL-Z1640-2似乎是ATL的有效治疗方法。需要进一步研究以开发更强效、保留LL-Z1640-2活性基序的化合物。© 2023 The Authors. eJHaem由英国血液学学会和约翰·威立出版有限公司发表。

Adult T-cell leukaemia/lymphoma (ATL) remains incurable. The NF-κB and interferon regulatory factor 4 (IRF4) signalling pathways are among the critical survival pathways for the progression of ATL. TGF-β-activated kinase 1 (TAK1), an IκB kinase-activating kinase, triggers the activation of NF-κB. The resorcylic acid lactone LL-Z1640-2 is a potent irreversible inhibitor of TAK1/extracellular signal-regulated kinase 2 (ERK2). We herein examined the therapeutic efficacy of LL-Z1640-2 against ATL. LL-Z1640-2 effectively suppressed the in vivo growth of ATL cells. It induced in vitro apoptosis and inhibited the nuclear translocation of p65/RelA in ATL cells. The knockdown of IRF4 strongly induced ATL cell death while downregulating MYC. LL-Z1640-2 as well as the NF-κB inhibitor BAY11-7082 decreased the expression of IRF4 and MYC at the protein and mRNA levels, indicating the suppression of the NF-κB-IRF4-MYC axis. The treatment with LL-Z1640-2 also mitigated the phosphorylation of p38 MAPK along with the expression of CC chemokine receptor 4. Furthermore, the inhibition of STAT3/5 potentiated the cytotoxic activity of LL-Z1640-2 against IL-2-responsive ATL cells in the presence of IL-2. Therefore, LL-Z1640-2 appears to be an effective treatment for ATL. Further studies are needed to develop more potent compounds that retain the active motifs of LL-Z1640-2.© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.