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

G. Minuesa; S. K. Albanese; A. Chow; A. Schurer; S.-M. Park; C. Z. Rotsides; J. Taggart; A. Rizzi; L. N. Naden; T. Chou; S. Gourkanti; D. Cappel; M. C. Passarelli; L. Fairchild; C. Adura; F. J. Glickman; J. Schulman; C. Famulare; M. Patel; J. K. Eibl; G. M. Ross; D. S. Tan; C. S. Leslie; T. Beuming; Y. Goldgur; J. D. Chodera; M. G. Kharas

doi:10.1038/s41467-019-10523-3

Cancer BiologyNature CommunicationsJun 19, 2019

Peer-reviewed journal article

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

G. Minuesa, S. K. Albanese, A. Chow, A. Schurer, S.-M. Park, C. Z. Rotsides, J. Taggart, A. Rizzi, L. N. Naden, T. Chou, S. Gourkanti, D. Cappel, M. C. Passarelli, L. Fairchild, C. Adura, F. J. Glickman, J. Schulman, C. Famulare, M. Patel, J. K. Eibl, G. M. Ross, D. S. Tan, C. S. Leslie, T. Beuming, Y. Goldgur, , M. G. Kharas

Abstract

The MUSASHI family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We found that the small molecule Ro 08-2750 (Ro) directly binds to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells resulted 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 demonstrated in vivo inhibition of c-MYC and reduced disease burden in a murine AML leukemia model. Thus, we have identified a small molecule that targets MSIs oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

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