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

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 moleculeRo 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 leukemiacells 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 burdenin a murine AML leukemia model. Thus, we identify a small moleculethat targets MSI’s oncogenic activity. Our study provides a framework for targeting RNA binding proteinsin cancer.