Valentina Gambacorta, PhD, Merus N.V., Utrecht, The Netherlands, explains the epigenetic mechanisms involved in leukemia relapse. Three different mechanisms all resulting in host immune system evasion can lead to relapse. Whilst the first mechanism is characterized by the loss of HLA class I molecules, the other two mechanisms involve loss of expression of HLA class II molecules and upregulation of immune checkpoint molecules. It has been shown that HLA class II expression can be rescued using demethylating agents or EZH2 inhibitors, which may be useful in patients who have lost HLA class II expression due to CTIIA promoter hypomethylation. In addition, a multi-omics analysis revealed that EZH2 was the cause of the epigenetic deregulation leading to leukemia relapse. Subsequent in vitro experiments demonstrated that it was not only possible to rescue HLA class II expression by treating malignant cells with inhibitors of complexes that EZH2 is a part of, but also to re-activate T-cell responses. This interview took place at the 2021 Relapse After HSCT² Workshop in New York, NY.