CMV Replication Drives IFNγ-Mediated Sensitization of AML Cells to Cytotoxic Killing Through the NKG2C-HLA-E Axis

Human cytomegalovirus (CMV) infection represents a significant risk factor for transplant recipients, including patients undergoing hematopoietic stem cell transplantation (HSCT). Interestingly, several studies have reported an association between early CMV reactivation and a reduced risk of leukemia relapse, particularly in acute myeloid leukemia (AML). Given that CMV profoundly shapes the natural killer (NK) cell compartment, a contribution of CMV-primed NK cells to this effect has been proposed. To explore this mechanism, we analyzed the relationship between NK cell functionality and CMV reactivation in the context of AML. Consistent with observations in peripheral blood, CMV-seropositive HSCT recipients displayed expanded NKG2Cpos NK cell populations within the bone marrow, characterized by high Granzyme B expression. CMV replication was associated with elevated plasma IFN{gamma} levels, which in vitro rendered AML cells more susceptible to apoptosis when co-cultured with peripheral blood mononuclear cells. Importantly, IFN{gamma} treatment modulated NK cell responses by inducing a variety of NK cell ligands including HLA-E on primary bone marrow-derived blasts and AML cell lines. In line with this, the activation of CMV-associated NKG2Cpos NK cells was enhanced upon stimulation with IFN{gamma}-pretreated AML cells. In summary, our findings demonstrate that CMV replication induces a transient increase in IFN{gamma} levels that influences both AML and NK cells, ultimately enhancing AML cell susceptibility to NK cell-mediated cytotoxicity initiated through the NKG2C-HLA-E axis. ImportancePrevious studies suggested that CMV reactivation after HSCT may reduce leukemia relapse in AML patients, but the underlying mechanism remained unclear. Here, we show that CMV replication induces IFN{gamma} release, which sensitizes AML cells to NK cell-mediated killing. This effect involves upregulation of HLA-E on AML cells and activation of expanded NKG2Cpos NK cells within the bone marrow. Our findings uncover a novel IFN{gamma}-dependent link between CMV replication and enhanced NK cell cytotoxicity in AML, suggesting that combining IFN{gamma} treatment with NK cell-based immunotherapy or NKG2A blockade could reduce post-HSCT relapse, even in CMV-negative patients.