Menin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML
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.
Authors
- Alina Hartmann (ORCID: https://orcid.org/0009-0002-0638-0000)
- Michal Remen (ORCID: https://orcid.org/0009-0000-2795-1453)
- Tobias Wertheimer (ORCID: https://orcid.org/0000-0002-8480-7391)
- Eric Metzger (ORCID: https://orcid.org/0000-0002-1394-1083)
- Melanie Boerries (ORCID: https://orcid.org/0000-0002-3670-0602)
- Melissa Zwick (ORCID: https://orcid.org/0009-0000-1482-2062)
- Cristina Toffalori (ORCID: https://orcid.org/0000-0002-8313-3057)
- Natalie Köhler (ORCID: https://orcid.org/0000-0002-7502-0431)
- Tobias F. Feuchtinger (ORCID: https://orcid.org/0000-0002-8517-9681)
- Monika Kuban
- Lukas M. Braun (ORCID: https://orcid.org/0000-0003-0770-4994)
- Viktor Fetsch (ORCID: https://orcid.org/0009-0006-2091-9999)
- Luca Vago (ORCID: https://orcid.org/0000-0003-4247-3175)
- Petya Apostolova (ORCID: https://orcid.org/0000-0002-3856-5109)
- Maike Hofmann (ORCID: https://orcid.org/0000-0001-8410-8833)
- Kristina Maas‐Bauer (ORCID: https://orcid.org/0000-0003-1788-2807)
- Khalid Shoumariyeh (ORCID: https://orcid.org/0000-0001-7969-1972)
- A. Stell (ORCID: https://orcid.org/0009-0002-5352-4871)
- Marco Punta (ORCID: https://orcid.org/0000-0002-0050-0676)
- H. T. Marc Timmers (ORCID: https://orcid.org/0000-0001-7062-1417)
- Franziska Blaeschke (ORCID: https://orcid.org/0000-0001-5770-4744)
- Geoffroy Andrieux (ORCID: https://orcid.org/0000-0002-5389-9481)
- Ezgi Ozyerli‐Goknar (ORCID: https://orcid.org/0000-0003-0202-8165)
- Christoph Rummelt (ORCID: https://orcid.org/0000-0002-6471-7030)
- Eyleen Corrales (ORCID: https://orcid.org/0000-0002-4767-1640)
- Simon M. Brandl (ORCID: https://orcid.org/0000-0002-1632-0127)
- Florian Perner (ORCID: https://orcid.org/0000-0003-1010-3321)
- Robert Zeiser (ORCID: https://orcid.org/0000-0001-6565-3393)
- Justus Duyster (ORCID: https://orcid.org/0000-0001-7325-7753)
- Susana Minguet (ORCID: https://orcid.org/0000-0001-8211-5538)
- Hosna Baniadam
- Alexander Zähringer (ORCID: https://orcid.org/0009-0006-1079-8214)
- Florian Heinrich Heidel (ORCID: https://orcid.org/0000-0003-2438-1955)
- Manoj Kumar Gupta (ORCID: https://orcid.org/0000-0003-1558-9471)
- Michael W.M. Kühn (ORCID: https://orcid.org/0000-0002-6434-9303)
- Sophie Pfeiffer (ORCID: https://orcid.org/0009-0005-3069-0940)
- M Andreis (ORCID: https://orcid.org/0009-0008-5080-3000)
- J L Farber (ORCID: https://orcid.org/0009-0002-2609-7827)
- Michael Lübbert
- Thomas Plenge
- Tabea Klaus (ORCID: https://orcid.org/0009-0004-1629-5664)
- Kathleen Grueter (ORCID: https://orcid.org/0009-0008-1350-0238)
- Lennard Frederik Schwöbel
- Lina Schlenke
Institutions
- Vita-Salute San Raffaele University (IT)
- University of Freiburg (DE)
- German Cancer Research Center (DE)
- University of Basel (CH)
- Johannes Gutenberg University Mainz (DE)
- Heidelberg University (DE)
- University Medical Center Freiburg (DE)
- University Hospital Heidelberg (DE)
- University Hospital of Basel (CH)
- Medizinische Hochschule Hannover (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Hopp Children's Cancer Center Heidelberg (DE)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Department of Biomedicine Basel (CH)
- European Molecular Biology Laboratory (DE)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
Publication Details
- Journal
- Blood
- Published
- 2025-10-27
- DOI
- https://doi.org/10.1182/blood.2025029712
- Citations
- 2
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 1.61