Abstract
Acute myeloid leukemia (AML) with chromosomal rearrangements involving the lysine methyltransferase 2A (KMT2A) gene and mutations in the nucleophosmin (NPM1) gene often relapse following allogeneic hematopoietic cell transplantation (allo-HCT). Targeting the interaction between menin and KMT2A with pharmacological menin-inhibitors disrupts the formation of oncogenic KMT2A complexes on the chromatin, thereby impairing abnormal self-renewal and promoting myeloid differentiation.
Beyond this anti-leukemic mechanism, we found that 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 enhanced the susceptibility of AML cells to T-cell–mediated elimination following allogeneic hematopoietic cell transplantation (allo-HCT) in mice, thereby enhancing the graft-versus-leukemia (GVL) effect in murine allograft models and human xenograft models. While menin-inhibition post allo-HCT resulted in a survival benefit, no increased histological acute graft-versus-host-disease (GVHD) score was observed throughout primary target organs.
In AML cells, ATAC-seq and REACTOME pathway enrichment analysis revealed enhanced viral transcription and translation along with the expression of multiple human endogenous retroviruses (HERVs) upon menin-inhibition. Consistent with elevated HERV expression, we observed increased accumulation of cytosolic double-stranded RNA and DNA. This was accompanied by activation of the STING pathway, which was linked to a broad induction of interferon-stimulated genes (ISGs) and elevated MHC-II levels. Moreover, we found that some AML cells without KMT2A-rearrangements or NPM1-mutations also upregulate MHC-II upon menin-inhibition, suggesting that menin-inhibitors may have broader applicability post allo-HCT across a wider range of patients.
Additionally, menin-inhibition directly enhanced the anti-tumor effector functions of donor T-cells. Transcriptomic profiling and high-dimensional flow cytometry revealed increased expression of IFN-γ, perforin, granzyme A, and T-cell activation markers upon menin-inhibitor exposure. Simultaneously, T-cell exhaustion and menin-KMT2A binding to genes that encode negative regulators of T-cell activation were reduced. These findings were validated at the functional level, demonstrating that menin-inhibitor-pretreated T-cells exhibit enhanced cytotoxicity against leukemic cells.
Our findings indicate that menin-inhibition enhances the GVL effect via the HERV/MHC-II axis in AML cells and promotes activation of donor T-cells, supporting its potential use as maintenance therapy after allo-HCT in clinical trials.
