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Homoharringtonine deregulates MYC transcriptional expression by directly binding NF-κB repressing factor

ABSTRACT: Homoharringtonine (HHT), a previously known protein synthesis inhibitor, has anti-myeloid leukemia effect and potentiates the therapeutic efficacy of anthracycline/cytarabine induction regimens for acute myeloid leukemia (AML) with favorable and intermediate prognosis, especially in t(8;21) subtype. Here we provide evidence to show that HHT inhibits the activity of leukemia-initiating cells (Lin-/Sca-1-/c-kit+, LICs) in t(8;21) murine leukemia model and exerts down-regulating effect on MYC pathway genes in human t(8;21) leukemia cells (Kasumi-1). By using biochemistry approach, NF-κB-repressing factor (NKRF) was discovered to be bound directly by HHT via the second double-strand RNA binding motif (DSRM2) domain, which is the nuclear localization signal (NLS) of NKRF. A series of deletion and mutagenesis experiments mapped HHT direct binding site to K479 and C480 amino acids in the DSRM2 domain. HHT treatment shifts NKRF from nucleus (including nucleoli) to cytoplasm through occupying the DSRM2 domain, strengthens p65-NKRF interaction, and interferes with the p65-p50 complex formation, thereby attenuating the transactivation activity of p65 on MYC gene. Moreover, HHT significantly decreases the expression of KIT, a frequently mutated and/or highly expressed gene in t(8;21) AML, in consistence with MYC downregulation. Our work has thus identified a mechanism different to, but in concert with, the classical mode of action of HHT and justifies its further clinical exploration in the treatment of AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE121175 | GEO | 2018/12/31

REPOSITORIES: GEO

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Project description:The t(8;21) translocation fuses the DNA binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape we measured genome-wide RUNX1- and RUNX1/ETO bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide re-distribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML. This SuperSeries is composed of the following subset Series: GSE29222: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [ChIP-Seq and DNAse-Hypersensitivity data] GSE29223: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [expression array data] GSE34540: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (ChIP-seq) GSE34594: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (Illumina expression) Refer to individual Series

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Homoharringtonine deregulates MYC transcriptional expression by directly binding NF-κB repressing factor

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