Menin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML
Abstract
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.
Article Details
Authors (44)
Viktor Fetsch
University Medical Center Freiburg, Freiburg, Germany
Lennard Schwöbel
1Department of Medicine I, Faculty of Medicine, University Medical Center, University of Freiburg, Freiburg, Germany
Ezgi Özyerli-Göknar
Anna-Verena Stell
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Marco Punta
5Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy
Thomas Plenge
Hannover Medical School, Hannover, Germany
Tabea Klaus
7Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
Manoj K. Gupta
Hannover Medical School, Hannover, Germany
Geoffroy Andrieux
Khalid Shoumariyeh
1Department of Medicine I, Faculty of Medicine, University Medical Center, University of Freiburg, Freiburg, Germany
Sophie Pfeiffer
1Department of Medicine I, Faculty of Medicine, University Medical Center, University of Freiburg, Freiburg, Germany
Eyleen Corrales
8Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Lina Schlenke
1Department of Medicine I, Faculty of Medicine, University Medical Center, University of Freiburg, Freiburg, Germany
Hosna Baniadam
1Department of Medicine I, Faculty of Medicine, University Medical Center, University of Freiburg, Freiburg, Germany
Simon M. Brandl
2Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany
Massimo Andreis
12Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
Michal Remen
12Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
Alina Hartmann
University Medical Center Freiburg, Freiburg, Germany
Kathleen Grueter
13German Cancer Research Center, Heidelberg, Germany
Melissa Zwick
Medical Center-University of Freiburg
Natalie Köhler
Monika Kuban
13German Cancer Research Center, Heidelberg, Germany
Eric Metzger
Christoph Rummelt
1Department of Medicine I, Faculty of Medicine, University Medical Center, University of Freiburg, Freiburg, Germany
Justus Duyster
Melanie Boerries
Maike Hofmann
Julian Färber
17Department of Pediatrics, University Medical Center Freiburg, Freiburg, Germany
Lukas M. Braun
Alexander Zähringer
1Department of Medicine I, Faculty of Medicine, University Medical Center, University of Freiburg, Freiburg, Germany
Michael Lübbert
10Department of Medicine I, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
Cristina Toffalori
IRCCS San Raffaele Scientific Institute, Milano, Italy
Luca Vago
Vita-Salute San Raffaele University, Italy
Florian H. Heidel
Susana Minguet
2Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany
Petya Apostolova
12Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
Tobias Feuchtinger
Kristina Maas-Bauer
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Franziska Blaeschke
13German Cancer Research Center, Heidelberg, Germany
Michael W. M. Kühn
1Department of Hematology and Oncology, Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
H. T. Marc Timmers
Tobias Wertheimer
Florian Perner
Robert Zeiser