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

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

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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.

t(821)AMLRUNX1-RUNX1T1KITeriocalyxin Bhomoharringtoninesynergistic effect

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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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

National Natural Science Foundation of ChinaShanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant SupportState Key Laboratory of Medical Genomics SupportJiading District Health Commission Chinese Medicine Youth Research Support

81670137201525012018022019-QN-ZYY-03

2024

10.1038/s41401-023-01196-2

中国药理学报(英文版)
中科院上海药物研究所

中国药理学报(英文版)

CSTPCD
影响因子：0.926
ISSN：1671-4083
年,卷(期)：2024.45(3)
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