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

• We found that menin-inhibition directly promoted anti-tumor effector functions of T cells by inducing cytokine and granzyme A/B production.

• We demonstrate a cascade of events by menin inhibition, causing activation of endogenous retroviruses, ISGs, cGAS-STING and MHC-II in AML.

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.