Hypermethylation of DNA impairs megakaryogenesis in delayed platelet recovery after allogeneic hematopoietic stem cell transplantation

Delayed platelet recovery (DPR) is a common and complex complication of hematopoietic stem cell transplantation (HSCT) with unclear mechanisms and poor patient outcomes. Emerging evidence suggests that impaired megakaryogenesis plays a critical role in the development of DPR. In this study, we report remarkable hypermethylation within CG islands of HSCs and megakaryocyte progenitor cells (MKPs) in patients with DPR. Treatment with the hypomethylating agent decitabine reduced methylated CG levels in MKPs and enhanced megakaryocyte production in mice. In addition, we found that DNMT3A negatively regulated megakaryogenesis in megakaryocyte lineages derived from primary HSCs. Transplantation with HSC-overexpressed DNMT3A impeded platelet engraftment following HSCT in mice. We further demonstrated that DNMT3A was directly bound to and methylated ETS1 and RUNX1 during megakaryogenesis. These findings highlight abnormal DNA methylation in DPR and indicate that hypomethylating agents may improve megakaryocyte proliferation and differentiation by targeting DNMT3A-mediated methylation.