Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.
Animals
Apoptosis
/ drug effects
Flavins
Gene Expression Profiling
Gene Expression Regulation, Leukemic
/ drug effects
Humans
Leukemia, Experimental
/ blood
Leukemia, Myeloid, Acute
/ blood
Male
Mice
Primary Cell Culture
Proto-Oncogene Proteins c-myc
/ metabolism
Pteridines
/ pharmacology
RNA
/ metabolism
RNA Recognition Motif
/ drug effects
RNA, Small Interfering
/ metabolism
RNA-Binding Proteins
/ antagonists & inhibitors
Transcriptome
/ drug effects
Tumor Cells, Cultured
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 06 2019
19 06 2019
Historique:
received:
19
11
2018
accepted:
16
05
2019
entrez:
21
6
2019
pubmed:
21
6
2019
medline:
10
7
2019
Statut:
epublish
Résumé
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.
Identifiants
pubmed: 31217428
doi: 10.1038/s41467-019-10523-3
pii: 10.1038/s41467-019-10523-3
pmc: PMC6584500
doi:
Substances chimiques
2,3,4,10-tetrahydro-7,10-dimethyl-2,4-dioxobenzo(g)pteridine
0
Flavins
0
MYC protein, human
0
Msi2h protein, mouse
0
Proto-Oncogene Proteins c-myc
0
Pteridines
0
RNA, Small Interfering
0
RNA-Binding Proteins
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2691Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : P30-CA008748
Pays : International
Organisme : NIH HHS
ID : S10 OD016432
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193842
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM121505
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101989
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL135564
Pays : United States
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