Combination regimen of granulocyte colony-stimulating factor and recombinant human thrombopoietin improves the curative effect on elderly patients with leukemia through inducing pyroptosis and ferroptosis of leukemia cells

Abstract

Leukemia ranks as the one of most common causes of death from tumor. 51.4% of patients with leukemia are over 65 years old. However, the median overall survival (OS) of elderly leukemia patients is less than one year. It is urgent to explore more effective treatments for elderly patients with leukemia. Our recent prospective phase II single-arm study has revealed that combination regimen of granulocyte colony-stimulating factor (G-CSF) and recombinant human thrombopoietin (rhTPO) could improve the curative effect on elderly patients with leukemia, yet the precise mechanism remains unknown. This study demonstrated that combination of G-CSF and rhTPO showed greater effect on suppressing leukemia growth than G-CSF or rhTPO alone in vitro and in vivo. Mechanistically, G-CSF induced pyroptosis through ELANE in leukemia cells. Besides, rhTPO triggered ferroptosis by EP300 in leukemia cells. Moreover, rhTPO suppressed glutathione peroxidase 4 (GPX4) expression to induce ferroptosis through blocking the interaction between EP300 and GPX4 gene promoter via associating with EP300. In summary, this study illuminated that combination regimen of G-CSF and rhTPO improved the curative effect on elderly patients with leukemia through inducing pyroptosis and ferroptosis of leukemia cells. Therefore, our results provided a theoretical basis for combination regimen of G-CSF and rhTPO treating leukemia and potential therapeutic targets for leukemia.

SETD1A‐mediated H3K4me3 methylation upregulates lncRNA HOXC‐AS3 and the binding of HOXC‐AS3 to EP300 and increases EP300 stability to suppress the ferroptosis of NSCLC cells

“…The recombinant human thrombopoietin induces ferroptosis in leukemia cells by EP300. 33 NSCLC cell ferroptosis was decelerated, evidenced by downregulated levels of iron, ACSL4, ROS, and MDA and upregulated levels of GPX4, SOD, and GSH, after upregulating EP300.…”

MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis

“…Then 10 µL CCK-8 solution (#C0037, Beyotime Biotechnology, Shanghai, China) at a 1/10 dilution was added in each well to incubate MM cells for 2 h at 37 °C, and absorbance at 450 nm was assayed by Multiscan MK3 (Thermo Fisher Scientific, Waltham, MA, USA) to identify cell viability or proliferation rate. Cell proliferation was measured after 1–3 days, while cell viability was determined in 24 h after PI treatment, as previously described [ 24 ].…”

Targeting ferroptosis for leukemia therapy: exploring novel strategies from its mechanisms and role in leukemia based on nanotechnology

“…In a phase 2 trial, Xiaoyu Liu and his team explored the potential anti-leukemia effects of a combination therapy involving granulocyte-colony stimulating factor (G-CSF), thrombopoietin (TPO), and low-dose chemotherapy in elderly patients with acute myeloid leukemia (AML) [ 215 ]. Their findings revealed that TPO triggers ferroptosis by inhibiting EP300-mediated GPX4 transcription, while G-CSF induces pyroptosis via neutrophil elastase, which in turn activates Gasdermin D (GSDMD) in AML cells [ 216 ].…”