1. Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.
- Author
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Minuesa G, Albanese SK, Xie W, Kazansky Y, Worroll D, Chow A, Schurer A, Park SM, Rotsides CZ, Taggart J, Rizzi A, Naden LN, Chou T, Gourkanti S, Cappel D, Passarelli MC, Fairchild L, Adura C, Glickman JF, Schulman J, Famulare C, Patel M, Eibl JK, Ross GM, Bhattacharya S, Tan DS, Leslie CS, Beuming T, Patel DJ, Goldgur Y, Chodera JD, and Kharas MG
- Subjects
- Animals, Apoptosis drug effects, Flavins, Gene Expression Profiling, Humans, Leukemia, Experimental blood, Leukemia, Myeloid, Acute blood, Male, Mice, Primary Cell Culture, Proto-Oncogene Proteins c-myc metabolism, Pteridines therapeutic use, RNA metabolism, RNA Recognition Motif drug effects, RNA, Small Interfering metabolism, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Transcriptome drug effects, Tumor Cells, Cultured, Gene Expression Regulation, Leukemic drug effects, Leukemia, Experimental drug therapy, Leukemia, Myeloid, Acute drug therapy, Pteridines pharmacology, RNA-Binding Proteins antagonists & inhibitors
- 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.
- Published
- 2019
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