CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials

Abstract Menin inhibitors have entered clinical trials for histone lysine methyltransferase 2 A (KMT2A) -rearranged and nucleophosmin 1 (NPM1) -mutant acute leukemias and are demonstrating promising activity. CRISPR base editor screening previously predicted several MEN1 (menin) mutations that have arisen in patients receiving SNDX-5613 and confer resistance. The extent to which MEN1 mutations will impact each menin inhibitor is mostly unknown. Here we show that CRISPR base editor screens can be