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

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

Nature communications (2019-06-21)

Gerard Minuesa, Steven K Albanese, Wei Xie, Yaniv Kazansky, Daniel Worroll, Arthur Chow, Alexandra Schurer, Sun-Mi Park, Christina Z Rotsides, James Taggart, Andrea Rizzi, Levi N Naden, Timothy Chou, Saroj Gourkanti, Daniel Cappel, Maria C Passarelli, Lauren Fairchild, Carolina Adura, J Fraser Glickman, Jessica Schulman, Christopher Famulare, Minal Patel, Joseph K Eibl, Gregory M Ross, Shibani Bhattacharya, Derek S Tan, Christina S Leslie, Thijs Beuming, Dinshaw J Patel, Yehuda Goldgur, John D Chodera, Michael G Kharas

PMID31217428

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.

MATERIALS

Product Number

Brand

Product Description

07-178

Sigma-Aldrich

Anti-Hox A9 Antibody, Upstate^®, from rabbit

A3854

Sigma-Aldrich

Anti-β-Actin−Peroxidase antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture

F1804

Sigma-Aldrich

ANTI-FLAG^® M2 antibody, Mouse monoclonal, 1 mg/mL, clone M2, affinity isolated antibody, buffered aqueous solution (50% glycerol, 10 mM sodium phosphate, and 150 mM NaCl, pH 7.4)