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@ARTICLE{Fetsch:305544,
      author       = {V. Fetsch and L. F. Schwöbel and E. Ozyerli-Goknar and
                      A.-V. Stell and M. Punta and T. Plenge and T. Klaus and M.
                      K. Gupta and G. Andrieux and K. Shoumariyeh and S. Pfeiffer
                      and E. Corrales and L. Schlenke and H. Baniadam and S. M.
                      Brandl and M. Andreis and M. Remen and A. Hartmann and K.
                      Grueter$^*$ and M. Zwick and N. Köhler and M. Kuban$^*$ and
                      E. Metzger and C. Rummelt and J. Duyster and M. Börries and
                      M. Hofmann and J. Färber and L. M. Braun and A. Zähringer
                      and M. Lübbert and C. Toffalori and L. Vago and F. H.
                      Heidel and S. Minguet and P. Apostolova and T. Feuchtinger
                      and K. Maas-Bauer and F. Blaeschke$^*$ and M. W. M. Kühn
                      and H. T. M. Timmers$^*$ and T. Wertheimer and F. Perner and
                      R. Zeiser},
      title        = {{M}enin inhibition enhances graft-versus-leukemia effects
                      by {T}-cell activation and endogenous retrovirus induction
                      in {AML}.},
      journal      = {Blood},
      volume       = {nn},
      issn         = {0006-4971},
      address      = {Washington, DC},
      publisher    = {American Society of Hematology},
      reportid     = {DKFZ-2025-02218},
      pages        = {nn},
      year         = {2025},
      abstract     = {Acute 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.},
      cin          = {D270 / FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)D270-20160331 / I:(DE-He78)FR01-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41144759},
      doi          = {10.1182/blood.2025029712},
      url          = {https://inrepo02.dkfz.de/record/305544},
}