MLL1 regulates cytokine-driven cell migration and metastasis

The interaction between MLL1 And Menin controls cancer cell proliferation, migration, and tumor progression. MLL1 depletion reduced 3D cell migration in vitro and led to lesser metastatic burden and prolonged survival in vivo. Mechanistically, MLL1-Menin interaction controls actin filament assembly and protrusion generation through IL-6-pSTAT3-Arp3 axis. MLL1-Menin interaction also controls TGF-β1-mediated acto-myosin contractility via Gli2-ROCK1/2-pMLC2 axis. Additionally, MLL1-menin inhibition decreased cell proliferation via a multitude of cell-cycle related pathways. Mice bearing MLL1-depleted tumors exhibited decreased significant lung metastatic burden when sacrificed at a set tumor size, indicating that MLL1 played a role in the invasion of tumor cells in vivo. Finally, MLL1-Menin inhibition was additive with standard chemotherapeutics, both in vitro and in vivo. Samples were divided into two groups. First group consisted of wild type MDA-MB-231 cells, cells transduced with MLL1 shRNA, and cells transduced with non-targeting scrambled shRNA control. Second group consisted of cells treated with MI-2-2 at two doses, cells treated with MI-503 at 3 doses, and cells treated with DMSO as a negative control. All conditions were performed as triplicates.