Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.

TitleSmall-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.
Publication TypeJournal Article
Year of Publication2019
AuthorsMinuesa G, Albanese SK, Xie W, Kazansky Y, Worroll D, Chow A, Schurer A, Park S-M, Rotsides CZ, Taggart J, Rizzi A, Naden LN, Chou T, Gourkanti S, Cappel D, Passarelli MC, Fairchild L, Adura C, J Glickman F, Schulman J, Famulare C, Patel M, Eibl JK, Ross GM, Bhattacharya S, Tan DS, Leslie CS, Beuming T, Patel DJ, Goldgur Y, Chodera JD, Kharas MG
JournalNat Commun
Volume10
Issue1
Pagination2691
Date Published2019 06 19
ISSN2041-1723
KeywordsAnimals, Apoptosis, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Humans, Leukemia, Experimental, Leukemia, Myeloid, Acute, Male, Mice, Primary Cell Culture, Proto-Oncogene Proteins c-myc, Pteridines, RNA, RNA Recognition Motif, RNA, Small Interfering, RNA-Binding Proteins, Transcriptome, Tumor Cells, Cultured
Abstract

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.

DOI10.1038/s41467-019-10523-3
Alternate JournalNat Commun
PubMed ID31217428
PubMed Central IDPMC6584500
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 GM121505 / GM / NIGMS NIH HHS / United States
P30-CA008748 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) / International

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