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

Nat Commun. 2019 Jun 19;10(1):2691. doi: 10.1038/s41467-019-10523-3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Flavins
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic / drug effects*
  • Humans
  • Leukemia, Experimental / blood
  • Leukemia, Experimental / drug therapy*
  • Leukemia, Myeloid, Acute / blood
  • Leukemia, Myeloid, Acute / drug therapy*
  • Male
  • Mice
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-myc / metabolism
  • Pteridines / pharmacology*
  • Pteridines / therapeutic use
  • RNA / metabolism
  • RNA Recognition Motif / drug effects
  • RNA, Small Interfering / metabolism
  • RNA-Binding Proteins / antagonists & inhibitors*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Transcriptome / drug effects
  • Tumor Cells, Cultured


  • 2,3,4,10-tetrahydro-7,10-dimethyl-2,4-dioxobenzo(g)pteridine
  • Flavins
  • MYC protein, human
  • Msi2h protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Pteridines
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • RNA