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Combination of eriocalyxin B and homoharringtonine exerts synergistic anti-tumor effects against t(8;21) AML

Acta Pharmacologica Sinica volume 45, pages 633–645 (2024)Cite this article

Abstract

Understanding the molecular pathogenesis of acute myeloid leukemia (AML) with well-defined genomic abnormalities has facilitated the development of targeted therapeutics. Patients with t(8;21) AML frequently harbor a fusion gene RUNX1-RUNX1T1 and KIT mutations as “secondary hit”, making the disease one of the ideal models for exploring targeted treatment options in AML. In this study we investigated the combination therapy of agents targeting RUNX1-RUNX1T1 and KIT in the treatment of t(8;21) AML with KIT mutations. We showed that the combination of eriocalyxin B (EriB) and homoharringtonine (HHT) exerted synergistic therapeutic effects by dual inhibition of RUNX1-RUNX1T1 and KIT proteins in Kasumi-1 and SKNO-1 cells in vitro. In Kasumi-1 cells, the combination of EriB and HHT could perturb the RUNX1-RUNX1T1-responsible transcriptional network by destabilizing RUNX1-RUNX1T1 transcription factor complex (AETFC), forcing RUNX1-RUNX1T1 leaving from the chromatin, triggering cell cycle arrest and apoptosis. Meanwhile, EriB combined with HHT activated JNK signaling, resulting in the eventual degradation of RUNX1-RUNX1T1 by caspase-3. In addition, HHT and EriB inhibited NF-κB pathway through blocking p65 nuclear translocation in two different manners, to synergistically interfere with the transcription of KIT. In mice co-expressing RUNX1-RUNX1T1 and KITN822K, co-administration of EriB and HHT significantly prolonged survival of the mice by targeting CD34+CD38− leukemic cells. The synergistic effects of the two drugs were also observed in bone marrow mononuclear cells (BMMCs) of t(8;21) AML patients. Collectively, this study reveals the synergistic mechanism of the combination regimen of EriB and HHT in t(8;21) AML, providing new insight into optimizing targeted treatment of AML.

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Fig. 1: EriB and HHT showed synergistic effects on cell viability and apoptosis in t(8;21) AML.
Fig. 2: EriB and HHT synergistically disturbed RUNX1-RUNX1T1 transcriptional function through impairing AETFC.
Fig. 3: EriB and HHT activated caspase-3 through activating the JNK pathway.
Fig. 4: EriB and HHT regulated KIT gene expression through dual inhibition of NF-κB pathway.
Fig. 5: Therapeutic efficacy of EriB and HHT in vivo.
Fig. 6: Therapeutic efficacy of EriB and HHT in primary t(8;21) AML cells.
Fig. 7: Schematic diagram of the synergistic mechanism of the EriB and HHT combination in t(8;21) AML.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81670137), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20152501), and State Key Laboratory of Medical Genomics Support (201802), and Jiading District Health Commission Chinese Medicine Youth Research Support (2019-QN-ZYY-03).

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  1. These authors contributed equally: Yi-chen Lei, Xin-jie Chen

Authors and Affiliations

  1. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Yi-chen Lei, Xin-jie Chen, Yu-ting Dai, Bing Dai, Ji-yue Wang, Miao-hui Li, Ping Liu, Han Liu, Kan-kan Wang, Lu Jiang & Bing Chen

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Contributions

BC conceived and supervised the study. YCL and XJC conducted the main experiments. BD, JYW, and MHL participated in the experiments. YTD performed RNA-seq and ChIP-seq analysis. PL, HL, and KKW gave the technical support. BC, XJC, YCL, and LJ wrote the paper. All authors have read and approved the final version of the manuscript.

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Correspondence to Lu Jiang or Bing Chen.

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Lei, Yc., Chen, Xj., Dai, Yt. et al. Combination of eriocalyxin B and homoharringtonine exerts synergistic anti-tumor effects against t(8;21) AML. Acta Pharmacol Sin 45, 633–645 (2024). https://doi.org/10.1038/s41401-023-01196-2

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