TY  - JOUR
AU  - Fetsch, Viktor
AU  - Schwöbel, Lennard Frederik
AU  - Ozyerli-Goknar, Ezgi
AU  - Stell, Anna-Verena
AU  - Punta, Marco
AU  - Plenge, Thomas
AU  - Klaus, Tabea
AU  - Gupta, Manoj K
AU  - Andrieux, Geoffroy
AU  - Shoumariyeh, Khalid
AU  - Pfeiffer, Sophie
AU  - Corrales, Eyleen
AU  - Schlenke, Lina
AU  - Baniadam, Hosna
AU  - Brandl, Simon M
AU  - Andreis, Massimo
AU  - Remen, Michal
AU  - Hartmann, Alina
AU  - Grueter, Kathleen
AU  - Zwick, Melissa
AU  - Köhler, Natalie
AU  - Kuban, Monika
AU  - Metzger, Eric
AU  - Rummelt, Christoph
AU  - Duyster, Justus
AU  - Börries, Melanie
AU  - Hofmann, Maike
AU  - Färber, Julian
AU  - Braun, Lukas M
AU  - Zähringer, Alexander
AU  - Lübbert, Michael
AU  - Toffalori, Cristina
AU  - Vago, Luca
AU  - Heidel, Florian H
AU  - Minguet, Susana
AU  - Apostolova, Petya
AU  - Feuchtinger, Tobias
AU  - Maas-Bauer, Kristina
AU  - Blaeschke, Franziska
AU  - Kühn, Michael W M
AU  - Timmers, Hermanus Theodorus Marcus
AU  - Wertheimer, Tobias
AU  - Perner, Florian
AU  - Zeiser, Robert
TI  - Menin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML.
JO  - Blood
VL  - nn
SN  - 0006-4971
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2025-02218
SP  - nn
PY  - 2025
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:41144759
DO  - DOI:10.1182/blood.2025029712
UR  - https://inrepo02.dkfz.de/record/305544
ER  -