Menin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML

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.