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| Status |
Public on Dec 31, 2018 |
| Title |
Homoharringtonine deregulates MYC transcriptional expression by directly binding NF-κB repressing factor |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
Kasumi-1 cells vehicle; Kasumi-1 cells treated with 20 nM HHT for 24h
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| Contributor(s) |
CHEN X, ZHANG W, CHEN B, XI W, LU Y, HUANG J, WANG Y, LONG J, WU S, ZHANG Y, WANG S, LI S, YIN T, LU M, XI X, LI J, WANG K, CHEN Z, CHEN S |
| Citation(s) |
30659143 |
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| Submission date |
Oct 12, 2018 |
| Last update date |
Apr 01, 2019 |
| Contact name |
Xinjie Chen |
| Organization name |
Shanghai Institute of Hematology
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| Street address |
RUIJIN ER ROAD
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| City |
SHANGHAI |
| State/province |
SHANGHAI |
| ZIP/Postal code |
210000 |
| Country |
China |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA495949 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE121175_RAW.tar |
29.2 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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