Background: The poor prognosis of acute myeloid leukemia (AML) is partly due to the immunosuppressive leukemia environment. A therapeutic approach to induce pyroptosis is promising to work on this issue. Pyroptosis, a form of inflammatory cell death, is capable to release pro-immune factors and enhance the infiltration and cytotoxicity of natural killer (NK) cells. Chemical drugs have been verified to enhance anti-tumor immunity by inducing pyroptosis. Arsenic trioxide (ATO), a clinical drug in leukemia, is reported to be effective to kill AML cells, but it’s still unclear about its mechanism in AML. Our research is aimed at exploring the ATO effect on pyroptosis induction and the anti-tumor immunity of NK cells in AML.Methods: Pyroptotic phenomenon was detected by confocal microscopy, Annexin-V / propidium iodide staining, LDH release assay, and western blotting; The release of cytokines was detected by SDS-PAGE, proteomic analysis, ELISA, etc.; AML xenograft models were established to explore the ATO effect in vivo and the anti-tumor effect of ATO treatment was identified by tumor-volume measurement, HE staining and KI67 staining; The activity of NK cells was evaluated by immunofluorescence, flow cytometric analysis, etc.; The differential expressed proteins were identified by quantitative proteomic analysis and western blotting.Results: We first discovered that ATO induced pyroptosis in AML cells and activated caspase-3/gasdermin E (GSDME) pathway to induce pyroptosis, and enhances the release of LDH, HMGB1, and IL-1β. Moreover, we revealed that ATO treatment promoted the proliferation, tumor-infiltration, and degranulation of NK cells in AML and its leukemia microenvironment. The further proteomic clues indicate the potential mechanisms of the ATO anti-leukemia effect in vivo.Conclusions: These findings indicate that ATO treatment induces pyroptosis via caspase-3/GSDME pathway, enhances the release of pro-inflammatory cytokines, and activates NK cells in AML. Our data identify what is to our knowledge the first clinical drug that induces pyroptosis in AML, revealing the potential anti-leukemic and pro-immune properties of ATO treatment in the leukemia microenvironment of AML, which may be beneficial in reducing the recurrence problems associated with the leukemia microenvironment.
Background: Acute lymphoblastic leukemia with MLL/AF4 rearrangement remains a major hurdle to improving outcomes. Gene network and circRNAs have been found to participate in tumorigenesis, while their roles in leukemia still need to be explored. Recent patents have shown that circRNAs exhibit the markers for the children ALL, although the target and related mechanism remain to be elucidated. Objective: This study aims to explore the possible targets and mechanisms of ALL with MLL-AF4 rearrangement. Methods: We first generated a gene network focusing on MLL-AF4 rearrangement. Cell viability was determined with Cell Counting Kit-8 assay. The cell apoptosis was tested by the Annexin V/PI assay. The RNA-protein complexes were analyzed by qRT-PCR, and the pathway proteins were analyzed by western blot. Results: This gene network was associated with biological processes, such as nucleic acid metabolism and immunity, indicating its key role in inflammation. We found that circ_0008012 was upregulated in MLL/AF4 ALL cells and regulated cell proliferation and apoptosis. Further computed simulation and RIP showed that IKKβ was the strongest protein in the NF-κB pathway binding with circ_0008012. As a result, possible regulation of circ_0008012 is suggested by binding IKKβ in the IKKα:IKKβ:IKKγ compound, which then phosphorylates IκB and activates NF-κB:p65:p300 compound in nuclear factor, thereby leading to leukemia. Conclusion: We identified a gene network for MLL/AF4 ALL. Moreover, circ_0008012 may be a therapeutic target for this subtype of ALL.
Background: The poor prognosis of acute myeloid leukemia (AML) is partly due to the immunosuppressive leukemia environment. A therapeutic approach to induce pyroptosis is promising to work on this issue. Pyroptosis, a form of inflammatory cell death, is capable to release pro-immune factors and enhance the infiltration and cytotoxicity of natural killer (NK) cells. Chemical drugs have been verified to enhance anti-tumor immunity by inducing pyroptosis. Arsenic trioxide (ATO), a clinical drug in leukemia, is reported to be effective to kill AML cells, but it’s still unclear about its mechanism in AML. Our research is aimed at exploring the ATO effect on pyroptosis induction and the anti-tumor immunity of NK cells in AML.Methods: Pyroptotic phenomenon was detected by confocal microscopy, Annexin-V / propidium iodide staining, LDH release assay, and western blotting; The release of cytokines was detected by SDS-PAGE, proteomic analysis, ELISA, etc.; AML xenograft models were established to explore the ATO effect in vivo and the anti-tumor effect of ATO treatment was identified by tumor-volume measurement, HE staining and KI67 staining; The activity of NK cells was evaluated by immunofluorescence, flow cytometric analysis, etc.; The differential expressed proteins were identified by quantitative proteomic analysis and western blotting.Results: We first discovered that ATO induced pyroptosis in AML cells and activated caspase-3/gasdermin E (GSDME) pathway to induce pyroptosis, and enhances the release of LDH, HMGB1, and IL-1β. Moreover, we revealed that ATO treatment promoted the proliferation, tumor-infiltration, and degranulation of NK cells in AML and its leukemia microenvironment. The further proteomic clues indicate the potential mechanisms of the ATO anti-leukemia effect in vivo.Conclusions: These findings indicate that ATO treatment induces pyroptosis via caspase-3/GSDME pathway, enhances the release of pro-inflammatory cytokines, and activates NK cells in AML. Our data identify what is to our knowledge the first clinical drug that induces pyroptosis in AML, revealing the potential anti-leukemic and pro-immune properties of ATO treatment in the leukemia microenvironment of AML, which may be beneficial in reducing the recurrence problems associated with the leukemia microenvironment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.