Post allo-HCT menin-inhibition enhances graft-versus-leukemia effects by endogenous retrovirus induction in AML and T-cell activation
Abstract
Abstract Acute myeloid leukemia (AML) with chromosomal rearrangements involving the lysine methyltransferase 2A (KMT2A) gene and mutations in the nucleophosmin (NPM1) gene often relapse following allogeneic hematopoietic cell transplantation (allo-HCT). Targeting the interaction between menin and KMT2A with pharmacological menin-inhibitors disrupts the formation of oncogenic KMT2A complexes on the chromatin, thereby impairing abnormal self-renewal and promoting myeloid differentiation. Beyond this anti-leukemic mechanism, we found that 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 enhanced the susceptibility of AML cells to T-cell–mediated elimination following allogeneic hematopoietic cell transplantation (allo-HCT) in mice, thereby enhancing the graft-versus-leukemia (GVL) effect in murine allograft models and human xenograft models. While menin-inhibition post allo-HCT resulted in a survival benefit, no increased histological acute graft-versus-host-disease (GVHD) score was observed throughout primary target organs. In AML cells, ATAC-seq and REACTOME pathway enrichment analysis revealed enhanced viral transcription and translation along with the expression of multiple human endogenous retroviruses (HERVs) upon menin-inhibition. Consistent with elevated HERV expression, we observed increased accumulation of cytosolic double-stranded RNA and DNA. This was accompanied by activation of the STING pathway, which was linked to a broad induction of interferon-stimulated genes (ISGs) and elevated MHC-II levels. Moreover, we found that some AML cells without KMT2A-rearrangements or NPM1-mutations also upregulate MHC-II upon menin-inhibition, suggesting that menin-inhibitors may have broader applicability post allo-HCT across a wider range of patients. Additionally, menin-inhibition directly enhanced the anti-tumor effector functions of donor T-cells. Transcriptomic profiling and high-dimensional flow cytometry revealed increased expression of IFN-γ, perforin, granzyme A, and T-cell activation markers upon menin-inhibitor exposure. Simultaneously, T-cell exhaustion and menin-KMT2A binding to genes that encode negative regulators of T-cell activation were reduced. These findings were validated at the functional level, demonstrating that menin-inhibitor-pretreated T-cells exhibit enhanced cytotoxicity against leukemic cells. Our findings indicate that menin-inhibition enhances the GVL effect via the HERV/MHC-II axis in AML cells and promotes activation of donor T-cells, supporting its potential use as maintenance therapy after allo-HCT in clinical trials.
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 Göknar
3University Medical Center, Department of Urology, Freiburg, Germany
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 Gupta
Montefiore Medical Center, Bronx, New York, United States
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 Brandl
2Albert-Ludwigs-University, Faculty of Biology, 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 Koehler
1University of Freiburg, Hematology, Oncology and Stem Cell Transplantation, Department of Medicine I, Faculty of Medicine, Freiburg, Germany
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 Faerber
16University Medical Center Freiburg, Department of Pediatrics, Freiburg, Germany
Lukas 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 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 Kuhn
H.Th. Marc Timmers
3University Medical Center, Department of Urology, Freiburg, Germany
Tobias Wertheimer
Florian Perner
Robert Zeiser