Homoharringtonine deregulates MYC transcriptional expression by directly binding NF-κB repressing factor.
Xin-Jie ChenWei-Na ZhangBing ChenWen-Da XiYing LuJin Yan HuangYue-Ying WangJun LongSong-Fang WuYun-Xiang ZhangShu WangSi-Xing LiTong YinMin LuXiao-Dong XiJun-Min LiKan-Kan WangZhu ChenSai-Juan ChenPublished in: Proceedings of the National Academy of Sciences of the United States of America (2019)
Homoharringtonine (HHT), a known protein synthesis inhibitor, has an anti-myeloid leukemia effect and potentiates the therapeutic efficacy of anthracycline/cytarabine induction regimens for acute myelogenous leukemia (AML) with favorable and intermediate prognoses, especially in the t(8;21) subtype. Here we provide evidence showing that HHT inhibits the activity of leukemia-initiating cells (Lin-/Sca-1-/c-kit+; LICs) in a t(8;21) murine leukemia model and exerts a down-regulating effect on MYC pathway genes in human t(8;21) leukemia cells (Kasumi-1). We discovered that NF-κB repressing factor (NKRF) is bound directly by HHT via the second double-strand RNA-binding motif (DSRM2) domain, which is the nuclear localization signal of NKRF. A series of deletion and mutagenesis experiments mapped HHT direct binding sites to K479 and C480 amino acids in the DSRM2 domain. HHT treatment shifts NKRF from the nucleus (including nucleoli) to the cytoplasm by occupying the DSRM2 domain, strengthens the p65-NKRF interaction, and interferes with p65-p50 complex formation, thereby attenuating the transactivation activity of p65 on the MYC gene. Moreover, HHT significantly decreases the expression of KIT, a frequently mutated and/or highly expressed gene in t(8;21) AML, in concert with MYC down-regulation. Our work thus identifies a mechanism of action of HHT that is different from, but acts in concert with, the known mode of action of this compound. These results justify further clinical testing of HHT in AML.
Keyphrases
- acute myeloid leukemia
- bone marrow
- allogeneic hematopoietic stem cell transplantation
- transcription factor
- induced apoptosis
- genome wide
- signaling pathway
- poor prognosis
- cell cycle arrest
- genome wide identification
- binding protein
- oxidative stress
- liver failure
- copy number
- crispr cas
- endoplasmic reticulum stress
- amino acid
- dna methylation
- pi k akt
- cell death
- lps induced
- intensive care unit
- low dose
- dendritic cells
- smoking cessation
- nucleic acid
- acute lymphoblastic leukemia
- toll like receptor
- inflammatory response