Background/Aims: Multiple myeloma (MM) is a common plasma cell malignancy that remains largely incurable, despite the plethora of treatments available. Recently developed inhibitors of the epigenetic protein menin (iMenin) are poised to significantly improve outcomes for many acute leukaemia patients, however, are not known to be active in other tumour types. We analysed DepMap and surprisingly discovered that many MM cell lines are highly dependent on menin and its key interacting partner MLL1 for proliferation. Therefore, this study aims to characterise the function of the menin/MLL1 complex in MM cells and test the efficacy of iMenin using a comprehensive panel of in vitro and in vivo models.
Methods: We characterised the effects of genetic and pharmacological inhibition of Menin in established MM cell lines and early passage patient-derived MM cells (physiologically relevant model). Impact on gene expression and epigenetic state was analysed by RNA-, ChIP- and chromatin conformation sequencing. Molecular determinants of menin response were identified by genome-wide CRISPR screening. The efficacy of iMenin alone or in combination with other clinically relevant drugs was assessed against our in vitro cell lines and in syngeneic and xenograft mouse models.
Results: iMenin therapy experiments in a panel of MM lines demonstrated that ~25% are exquisitely sensitive to iMenin, with an additional ~40% showing a significant response. Gene expression and chromatin profiling studies identified the master myeloma cell identity factor IRF4 as a key downstream target of menin. Sensitivity is characterised by the abundant deposition of the menin/MLL1 complex at the super-enhancer of IRF4, with iMenin treatment resulting in eviction of menin/MLL1 from chromatin and concomitant suppression of IRF4 and its target genes. In parallel, we also applied CRISPR screening, which identified the EP300/CREBBP/NCOR1 axis as a key modulator of iMenin sensitivity. To further advance the translational potential of iMenin, we tested several combination strategies. Among the most effective, the combination of menin and EP300/CREBBP inhibitors demonstrated synergistic activity against cell lines and the syngeneic in vivo Vk*MYC model. Molecular analysis substantiated deep and synergistic suppression of IRF4 potentiated by the combination. Taken together, menin is a promising clinical target in MM.