Viktor Fetsch, Lennard Frederik Schwöbel, Ezgi Ozyerli‐Goknar, A. Stell, Marco Punta, Thomas Plenge, Tabea Klaus, Manoj Kumar Gupta, Geoffroy Andrieux, Khalid Shoumariyeh, Sophie Pfeiffer, Eyleen Corrales, Lina Schlenke, Hosna Baniadam, Simon M. Brandl, M Andreis, Michal Remen, Alina Hartmann, Kathleen Grueter, Melissa Zwick, Natalie Köhler, Monika Kuban, Eric Metzger, Christoph Rummelt, Justus Duyster, Melanie Boerries, Maike Hofmann, J L Farber, Lukas M. Braun, Alexander Zähringer, Michael Lübbert, Cristina Toffalori, Luca Vago, Florian H. Heidel, Susana Minguet, Petya Apostolova, Tobias Feuchtinger, Kristina Maas‐Bauer, Franziska Blaeschke, Michael W.M. Kühn, H. T. Marc Timmers, Tobias Wertheimer, Florian Perner, Robert Zeiser
ABSTRACT: Acute myeloid leukemia (AML) carrying chromosomal rearrangements involving the lysine methyltransferase 2A (KMT2A) gene frequently relapse after allogeneic hematopoietic cell transplant (allo-HCT). Pharmacological blockade of the menin-KMT2A interaction disrupts the assembly of oncogenic KMT2A complexes on chromatin, thereby attenuating aberrant self-renewal and inducing myeloid differentiation. We found that beyond this antileukemic mechanism, menin inhibition induced class II transactivator and major histocompatibility complex II (MHC-II) expression in KMT2A-rearranged and NPM1-mutated AML cells in vitro and in vivo. Increased MHC-II expression sensitized AML cells to T-cell-mediated elimination after allo-HCT in mice. Menin inhibition also increased MHC-II expression on primary human AML cells, and enhanced the graft-versus-leukemia (GVL) effect in human xenograft models. Mechanistically, menin inhibition increased expression of multiple human endogenous retroviruses (HERV), leading to consecutive interferon-stimulated gene upregulation and enhanced MHC-II expression. Additionally, menin inhibition directly promoted antitumor effector functions of donor T cells, causing increased tumor necrosis factor-alfa, interferon-gamma, perforin, and granzyme A/B production and cytolytic activity. T-cell exhaustion and menin-KMT2A binding to genes encoding for negative regulators of T-cell activation were reduced by menin inhibition. These findings indicate that menin inhibition enhances the GVL effect via the HERV/MHC-II axis in AML cells and promotes cytotoxicity of donor T cells, which provides a rationale for a clinical trial using menin inhibition as maintenance after allo-HCT.