Myelodysplastic syndrome (MDS) is a myeloid malignancy characterized by ineffective hematopoiesis and high risk of progression to leukemia. The current standard first-line therapy for high risk MDS includes the use of DNA hypomethylating agents (HMAs). Despite our incomplete understanding of the underlying mechanisms of HMA therapy, its effectiveness in extending overall survival and temporarily improving quality of life in MDS patients is well-documented, even achieving complete morphological responses and transfusion independency in a subset of patients. However, fifty percent of MDS patients exhibit primary resistance whereby they have no therapeutic response to HMAs, and in MDS patients with an initial response to HMAs, chronic treatment eventually leads to secondary resistance. Therefore, resistance to HMAs represent a major clinical challenge for MDS patients, as patients developing resistance to HMA have limited therapeutic options and the prognosis is dismal after HMA failure.

Our current projects aim to define the clonal evolution trajectories together with the changes in epigenetic profiles of malignant cells contributing to therapy resistance in HMA-treated patients. By doing so, we aim at setting the foundation for the development of new therapeutic approaches for the treatment of MDS patients showing resistance to HMAs