Abstract
Menin is a scaffolding protein that interacts with context-specific partners to regulate gene expression. In rearranged mixed-lineage leukemia, Menin-MLL interactions drive leukemogenesis and Menin inhibitors have been FDA approved for these cancers. We previously reported that Menin promotes oncogenic phenotypes in Ewing sarcoma (EwS). Here, we sought to define EwS-specific functions of Menin and determine if Menin inhibitors could be therapeutically leveraged for these tumors. Genetic KO of Menin had no effect on EwS cell proliferation in vitro, but metastatic potential of Menin-depleted cells in vivo was impaired. Transcriptional profiling of Menin-KO cells in vitro showed reproducible downregulation of MYC signature genes and upregulation of developmental programs. Conversely, transcriptional rewiring of developmental genes and restoration of MYC target gene expression were evident in tumors that arose from Menin-KO cells. Exposing EwS cells to the Menin inhibitor VTP50469 (revumenib) inhibited expression of MYC targets, and coimmunoprecipitation studies detected Menin-MYC interactions that were partially disrupted by the drug. Metastatic colonization of disseminated EwS cells in vivo was significantly inhibited in mice fed VTP50469 chow. Together these findings implicate Menin as a mediator of EwS metastasis and suggest that Menin inhibitors warrant investigation as novel therapeutics for patients with high-risk disease.
Authors
Katherine A. Braun, Nicolas M. Garcia, Mohamed A. Ahmed, Darleen S. Tu, Stephanie I. Walter, Emma D. Wrenn, Megan E.B. Dean, Neerja Katiyar, Elizabeth R. Lawlor
Figure 2
MEN1-KO EwS cells have altered expression of proliferation and differentiation programs.
