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 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.