Targeting the epigenetic adaptor protein menin in multiple myeloma

The interaction between the epigenetic proteins Menin and MLL1 is critical for sustaining the expression of self-renewal genes in specific subsets of acute leukemias. Disrupting the Menin-MLL1 interaction with Menin inhibitors (iMenin) is showing promising overall response rates in leukemia clinical trials, however, iMenin are not known to be active in other cancers. We analysed DepMap and discovered that many multiple myeloma (MM) cell lines are highly dependent on Menin/MLL1 for proliferation. MM is a common plasma cell malignancy that remains largely incurable, despite the plethora of treatments available. The objectives of our study are to understand the role of the Menin/MLL1 complex in MM, determine the efficacy of iMenin in MM pre-clinical models and identify biomarkers of response to enable the rapid and successful translation of iMenin into the myeloma setting. To assess the efficacy of iMenin in MM, we performed growth assays across 13 commercially available cell lines and 9 early passage patient-derived MM cells (physiologically relevant model). We found that ~30% were highly sensitive to iMenin with a substantial impact on viability and proliferation, with an additional ~40% showing a significant anti-proliferative response. Sensitivity was significantly correlated with the absence of the MYC t(8;14) translocation. Importantly, iMenin showed in vivo efficacy in a xenograft and in the syngeneic Vk*MYC-32052 model of MM. RNA-, ChIP- and chromatin conformation sequencing found that iMenin sensitivity was characterized by the deposition of Menin/MLL1 at the super-enhancer of IRF4, with iMenin evicting Menin/MLL1 from chromatin and suppressing IRF4 and its target genes. Genome-wide CRISPR screening was performed to identify the molecular determinants of iMenin response in MM. This 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 was the combination of Menin and EP300/CREBBP inhibitors, which demonstrated synergistic activity even in models which were unresponsive to the single-agents, including JJN3 cells in vitro and the syngeneic in vivo Vk*MYC-14551 model. Molecular analyses uncovered deep suppression of IRF4, via disruption of the canonical IRF4 super-enhancer, as the mechanism underpinning the synergy between Menin and EP300/CREBBP inhibitors. Taken together, Menin regulates the pan-myeloma essential transcription factor IRF4 and is a promising and clinically actionable target in MM.