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.
Highlights
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia
We performed MicroScale Thermophoresis assay (MST) and found that Ro directly interacted with MSI2 with a KD of 12.3 ± 0.5 μM (Fig. 1d)
These data suggest that Ro directly interacts with the MSI2 RNA-recognition motif 1 (RRM1) and competes with RNA binding
Summary
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. 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. RNA-binding proteins (RBPs) play critical roles in cell homeostasis by controlling gene expression posttranscriptionally. The relevance and requirement for MSI2’s function in leukemia was demonstrated by a series of depletion and overexpression studies in both mouse and human systems. Subsequent studies found a role for MSI2 in maintaining the MDS stem cell in a NUP98-HOXD13 mouse model and inducible forced expression of MSI2 drove a more aggressive form of MDS/ AML that was dependent on sustained MSI2 induction[28]. We demonstrate that Ro has efficacy in inhibiting myeloid leukemogenesis in both in vitro and in vivo models
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