Post allo-HCT menin-inhibition enhances graft-versus-leukemia effects by endogenous retrovirus induction in AML and T-cell activation

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.

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Journal
Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-5862
Primary Topic
Acute Myeloid Leukemia Research
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article
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article

Post allo-HCT menin-inhibition enhances graft-versus-leukemia effects by endogenous retrovirus induction in AML and T-cell activation

Alina Hartmann, Michal Remen, Natalie Koehler, Tobias Wertheimer et al.
Blood
Acute Myeloid Leukemia Research
article

Post allo-HCT menin-inhibition enhances graft-versus-leukemia effects by endogenous retrovirus induction in AML and T-cell activation

Alina Hartmann, Michal Remen, Natalie Koehler, Tobias Wertheimer, Eric Metzger, Melanie Boerries, Melissa Zwick, Jennifer Faerber, Cristina Toffalori, Tobias F. Feuchtinger, Monika Kuban, Justus Duyster, Lukas M. Braun, Viktor Fetsch, Luca Vago, Petya Apostolova, Maike Hofmann, Kristina Maas‐Bauer, Khalid Shoumariyeh, A. Stell, Marco Punta, H. T. Marc Timmers, Franziska Blaeschke, Geoffroy Andrieux, Christoph Rummelt, Eyleen Corrales, Simon M. Brandl, Florian Perner, Robert Zeiser, Manoj Kumar Gupta, Susana Minguet, Hosna Baniadam, Alexander Zähringer, Florian Heinrich Heidel, Michael W.M. Kühn, Sophie Pfeiffer, M Andreis, Michael Lübbert, Thomas Plenge, Tabea Klaus, Kathleen Grueter, Lennard Frederik Schwöbel, Lina Schlenke, Ezgi Göknar
article en

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.

BloodVol. 146(Supplement 1)
Vita-Salute San Raffaele University (IT), University of Freiburg (DE), German Cancer Research Center (DE), Johannes Gutenberg University Mainz (DE), Heidelberg University (DE), Catholic University of Applied Sciences Freiburg (DE), University Medical Center Freiburg (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)
Openalex Percentile: Top 48%
Acute Myeloid Leukemia Research
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