%0 Journal Article
%A Fetsch, Viktor
%A Schwöbel, Lennard Frederik
%A Ozyerli-Goknar, Ezgi
%A Stell, Anna-Verena
%A Punta, Marco
%A Plenge, Thomas
%A Klaus, Tabea
%A Gupta, Manoj K
%A Andrieux, Geoffroy
%A Shoumariyeh, Khalid
%A Pfeiffer, Sophie
%A Corrales, Eyleen
%A Schlenke, Lina
%A Baniadam, Hosna
%A Brandl, Simon M
%A Andreis, Massimo
%A Remen, Michal
%A Hartmann, Alina
%A Grueter, Kathleen
%A Zwick, Melissa
%A Köhler, Natalie
%A Kuban, Monika
%A Metzger, Eric
%A Rummelt, Christoph
%A Duyster, Justus
%A Börries, Melanie
%A Hofmann, Maike
%A Färber, Julian
%A Braun, Lukas M
%A Zähringer, Alexander
%A Lübbert, Michael
%A Toffalori, Cristina
%A Vago, Luca
%A Heidel, Florian H
%A Minguet, Susana
%A Apostolova, Petya
%A Feuchtinger, Tobias
%A Maas-Bauer, Kristina
%A Blaeschke, Franziska
%A Kühn, Michael W M
%A Timmers, Hermanus Theodorus Marcus
%A Wertheimer, Tobias
%A Perner, Florian
%A Zeiser, Robert
%T Menin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML.
%J Blood
%V nn
%@ 0006-4971
%C Washington, DC
%I American Society of Hematology
%M DKFZ-2025-02218
%P nn
%D 2025
%X Acute myeloid leukemia (AML) carrying chromosomal rearrangements involving the lysine methyltransferase 2A (KMT2A) gene frequently relapse after allogeneic hematopoietic cell transplantation (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 anti-leukemic mechanism, menin-inhibition induced CIITA and 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 (HERVs) leading to consecutive interferon-stimulated gene (ISG) upregulation and enhanced MHC-II expression. Additionally, menin-inhibition directly promoted anti-tumor effector functions of donor T-cells causing increased TNF-α, IFN-ү, 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41144759
%R 10.1182/blood.2025029712
%U https://inrepo02.dkfz.de/record/305544