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000305544 1001_ $$00009-0006-2091-9999$$aFetsch, Viktor$$b0
000305544 245__ $$aMenin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML.
000305544 260__ $$aWashington, DC$$bAmerican Society of Hematology$$c2025
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000305544 520__ $$aAcute 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.
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000305544 7001_ $$aSchwöbel, Lennard Frederik$$b1
000305544 7001_ $$00000-0003-0202-8165$$aOzyerli-Goknar, Ezgi$$b2
000305544 7001_ $$00009-0002-5352-4871$$aStell, Anna-Verena$$b3
000305544 7001_ $$00000-0002-0050-0676$$aPunta, Marco$$b4
000305544 7001_ $$aPlenge, Thomas$$b5
000305544 7001_ $$00009-0004-1629-5664$$aKlaus, Tabea$$b6
000305544 7001_ $$aGupta, Manoj K$$b7
000305544 7001_ $$aAndrieux, Geoffroy$$b8
000305544 7001_ $$aShoumariyeh, Khalid$$b9
000305544 7001_ $$00009-0005-3069-0940$$aPfeiffer, Sophie$$b10
000305544 7001_ $$00000-0002-4767-1640$$aCorrales, Eyleen$$b11
000305544 7001_ $$aSchlenke, Lina$$b12
000305544 7001_ $$aBaniadam, Hosna$$b13
000305544 7001_ $$00000-0002-1632-0127$$aBrandl, Simon M$$b14
000305544 7001_ $$00009-0008-5080-3000$$aAndreis, Massimo$$b15
000305544 7001_ $$00009-0000-2795-1453$$aRemen, Michal$$b16
000305544 7001_ $$aHartmann, Alina$$b17
000305544 7001_ $$00009-0008-1350-0238$$aGrueter, Kathleen$$b18
000305544 7001_ $$00009-0000-1482-2062$$aZwick, Melissa$$b19
000305544 7001_ $$00000-0002-7502-0431$$aKöhler, Natalie$$b20
000305544 7001_ $$0P:(DE-He78)12ef1af084ff6115819d7b3b36df26fe$$aKuban, Monika$$b21$$udkfz
000305544 7001_ $$00000-0002-1394-1083$$aMetzger, Eric$$b22
000305544 7001_ $$00000-0002-6471-7030$$aRummelt, Christoph$$b23
000305544 7001_ $$00000-0001-7325-7753$$aDuyster, Justus$$b24
000305544 7001_ $$aBörries, Melanie$$b25
000305544 7001_ $$00000-0001-8410-8833$$aHofmann, Maike$$b26
000305544 7001_ $$00009-0002-2609-7827$$aFärber, Julian$$b27
000305544 7001_ $$aBraun, Lukas M$$b28
000305544 7001_ $$00009-0006-1079-8214$$aZähringer, Alexander$$b29
000305544 7001_ $$aLübbert, Michael$$b30
000305544 7001_ $$00000-0002-8313-3057$$aToffalori, Cristina$$b31
000305544 7001_ $$00000-0003-4247-3175$$aVago, Luca$$b32
000305544 7001_ $$00000-0003-2438-1955$$aHeidel, Florian H$$b33
000305544 7001_ $$00000-0001-8211-5538$$aMinguet, Susana$$b34
000305544 7001_ $$aApostolova, Petya$$b35
000305544 7001_ $$00000-0002-8517-9681$$aFeuchtinger, Tobias$$b36
000305544 7001_ $$00000-0003-1788-2807$$aMaas-Bauer, Kristina$$b37
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000305544 7001_ $$aKühn, Michael W M$$b39
000305544 7001_ $$0P:(DE-He78)a77f61c7d4ca6aa1f9adc620eed66f3d$$aTimmers, Hermanus Theodorus Marcus$$b40$$udkfz
000305544 7001_ $$aWertheimer, Tobias$$b41
000305544 7001_ $$00000-0003-1010-3321$$aPerner, Florian$$b42
000305544 7001_ $$aZeiser, Robert$$b43
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