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. 2022 Mar 4;21:66. doi: 10.1186/s12943-022-01541-9

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© The Author(s) 2022, corrected publication 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 6 — Gilteritinib upregulated NKG2DL expression via the noncanonical NF-κB2/Rel B signalling pathway. A MOLM-13 and MV4-11 cells were treated with IC25 gilteritinib for 24 h followed by real-time PCR. The diagrams showed that gilteritinib elevated the mRNA expression of NF-κB upstream and downstream target genes. B Western blotting on the MOLM-13 and MV4-11 cells pre-treated with IC25 gilteritinib for 24 h. The protein levels of p100, p52, and p65 and the phosphorylation of p100 and p65 in MOLM-13 and MV4-11 cells were significantly increased with gilteritinib treatment. C MOLM-13 and MV4-11 cells were treated with 10 nM TNF-a for 24 h or 2.5uM BAY11-7082 for 12 h following IC25-gilteritinib for 24 h. The gilteritinib-induced upregulation of NKG2DLs in AML cells was similar to that induced by TNF-α but was significantly suppressed by the NF-κB inhibitor BAY 11–7082 at the protein level. D MOLM-13 and MV4-11 cells were transfected with si-NF-kB2 for 72 h and then incubated with IC25-gilteritinib for 24 h. Silencing NF-κB2 downregulated gilteritinib-induced NKG2DL expression in AML cells, indicating that gilteritinib regulated NKG2DL expression via the noncanonical NF-κB2/Rel B signalling pathway. E ChIP analysis showed that NF-κB2 binds to the MICB promoter. F In the absence or presence of 72-h siRNA (siRNA-NC or siRNA- NF-κB2) transfection, MOLM-13 cells were transfected with luciferase reporter vectors (PGL3-vector or PGL3-MICB) using Lipofectamine 3000. MOLM-13 cells were treated with or without IC25-gilteritinib for 24 h, and then the luciferase activity was detected by a dual luciferase assay system. The histogram showed that RLU represents the luciferase activity normalized to pRL-TK luciferase activity for each group. Luciferase assays showed that NF-κB2 was able to activate the transcription of MICB. The data presented are derived from the results of three independent experiments. G, gilteritinib; Con, control; RLUs, relative light units; P-control, pGL3-control vector; ns, not significant. * p < 0˜.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001