Title | Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Minuesa 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 |
Journal | Nat Commun |
Volume | 10 |
Issue | 1 |
Pagination | 2691 |
Date Published | 2019 06 19 |
ISSN | 2041-1723 |
Keywords | Animals, 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. |
DOI | 10.1038/s41467-019-10523-3 |
Alternate Journal | Nat Commun |
PubMed ID | 31217428 |
PubMed Central ID | PMC6584500 |
Grant List | P30 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 |
Submitted by bel2021 on December 2, 2019 - 10:13am