Defining mechanisms of action of Menin inhibition in AML

Dana-Farber Cancer Inst, Boston MA

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Abstract

Abstract Project 3 Acute myeloid leukemia (AML), and specifically KMT2A-rearranged (KMT2A-r) and NPM1 mutant AML, remain devasting disease with an overall poor prognosis for high risk pediatric and adult patients. AML is characterized by aberrant transcriptional programs caused by dysregulated chromatin associated complexes. In particular, the histone methyltransferase KMT2A and members of its large chromatin associated complex, including Menin and DOT1L, are responsible for the stable aberrant expression of developmental genes, such as homeotic (HOX) genes and MEIS1, which are key to the oncogenic program. Pharmacologic inhibition of the Menin-KMT2A interaction by Menin inhibitors is currently in being assessed clinical trials has shown remarkable efficacy in KMT2A-r and NPM1 mutant AML, providing potential new treatment options. While these promising clinical results further support the importance of these key chromatin associated complexes, the lack of mechanistic understanding currently limits further advances in the development of new treatments for this disease. Based on recent data from our labs, we hypothesize that KMT2A and Menin containing complexes establish distinct chromatin conformations that establish the oncogenic transcriptional program and that these distinct complexes exist at specific loci. We further hypothesize that beyond blocking the Menin-KMT2A interaction, combination with inhibitors of other complex members (DOT1L or KAT6A) or by degrading Menin through the use of proteolysis targeting chimeras (PROTACs) would lead to improved efficacy. Specifically, in Aim 1, we will use genetically engineered cell line models and advanced sequencing-based methods to interrogate the chromatin structure induced and maintained by KMT2A and Menin dependent complexes. In preliminary data, we have identified unique genomic conformations that support long range interactions between distinct Menin complexes to support transcription at specific genes important for AML. We will study the precise composition of these protein complexes using mass spectrometry-based proteomics approaches. In Aim 2, we will test the hypothesis that the ubiquitin ligase UBR5 is critically involved in the stability of Menin- and KMT2A-containing chromatin complexes. Based on our observation that UBR5 contributes to the destabilization of Menin and KMT2A post Menin inhibitor treatment, we will interrogate how UBR5 mediated stability impacts chromatin occupancy, chromatin conformation and transcriptional output mediated by RNAPII. In Aim 3, we will test the hypothesis that combinations of drugs targeting multiple components of these epigenetic enzymes or the use of newly available Menin directed PROTACs will enhance the efficacy of targeting these AML defining chromatin complexes and thereby oncogenic transcription.