UBR5 Mediates Menin Inhibitor Dependent Menin/KMT2A Complex Stability [RNA-seq]

The chromatin adaptor protein Menin (MEN1) is required by acute leukemias driven by mixed lineage leukemia 1 gene rearrangements (KMT2A-r) for sustained leukemogenesis. Menin inhibitors (MIs), which disrupt the Menin-KMT2A interface leading to downregulation of Menin-KMT2A oncogenic transcriptional programs, have shown promising results in recent clinical trials treating acute myeloid leukemia (AML). Decreased Menin protein stability has been observed following treatment with several MIs though proteasomal degradation, though the biological mechanisms that control Menin stability are not well understood. Here we interrogate and compare five clinical MIs and two pre-clinical compounds to characterize the mechanism by which MIs induce Menin degradation and demonstrate that the loss of the Menin-KMT2A interaction results in decreased protein stability of Menin and KMT2A. We have identified the HECT E3 ubiquitin ligase UBR5 as a regulator of Menin protein stability and demonstrate that UBR5 binds to similar sites as the Menin/KMT2A complex on chromatin. Loss of UBR5 leads to transcriptional rescue of Menin-KMT2A target genes leading to decreased sensitivity to all MIs. Thus, we present UBR5 as an important regulator of Menin/KMT2A complex stability and Menin destabilization/subcellular localization as a designable feature of Menin inhibition targeting KMT2A-r leukemias.