CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials
Year: 2026
Type: article
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 leveraged to profile the MEN1 mutations that may impact five different menin inhibitors in clinical trials. We identify shared (M327I/V/T, G331D) and inhibitor-specific (C334R, E368K/V, V372A) resistance mutations. Co-crystal structures of menin bound to each menin inhibitor suggest resistance mechanisms related to how each inhibitor engages the KMT2A binding pocket of menin. Orthogonal in vitro and in vivo MEN1 mutation generation under therapeutic pressure suggest the MEN1 mutations identified with CRISPR base editor screening are likely to arise and impact all menin inhibitors.
Source: Nature Communications
Authors: Wallace Bourgeois, Hannah E. Rice, Daniela V. Wenge, Florian Perner, Hong Yue, Brandon D. Regalado, George Wan, Jan C. Schroeder, Alba Sommerschield, Charlie Hatton, Shivendra Singh, Sweta Singh, Shipra Bijpuria, Brian M. McKeever, William H. Miller, Jordan F. Safer, Sumaiya Iqbal, Jennifer A. Perry, Eric S. Fischer, John G. Doench, Gerard M. McGeehan, Jevon A. Cutler, Scott A. Armstrong
Institutions: Boston Children's Hospital, Harvard University, Dana-Farber Cancer Institute, Medizinische Hochschule Hannover, Syngene International (India), Broad Institute, Massachusetts Institute of Technology, Syndax Pharmaceuticals (United States), Oregon Health & Science University, OHSU Knight Cancer Institute, Dana-Farber/Harvard Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1120188257, Novel Therapeutic Strategies in Human Myeloid Leukemias, FOR 5659: TARGETMPN: Zielgerichtetes Vorgehen gegen KrankheitsPersistenz und Progression bei myeloproliferativen Neoplasien (MPN), G1915563957, G2019256308, G2020571142, G2383814189, G2390440901, Aberrante ChromatinKomplexe als Zielstrukturen in klonaler Hämatopoese und PräLeukämie., G2541397611, G401456990, G4534695922, G4841831832, G612573404, Umkehrung der epigenetischen Resistenz gegenüber Inhibitoren der MLLMeninInteraktion in der akuten myeloischen Leukämie, SPORE in Myeloid Malignancies, G7546166877, G7706152136, G8430490084, G9000011189, G9000011884, G9000014437, G9000037087, G9000070958, G9000075951, G9000303215, G918485426
OpenAlex ID: W7160604095