Tang Yaqiong, Song Xiaofei, Zhang Ziyan, Yao Yifang, Pan Tingting, Qi Jiaqian, Xia Lijun, Wu Depei, Han Yue
National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
Sci Adv. 2025 May 9;11(19):eads3630. doi: 10.1126/sciadv.ads3630. Epub 2025 May 7.
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.
延迟血小板恢复（DPR）是造血干细胞移植（HSCT）常见且复杂的并发症，其机制不明，患者预后较差。新出现的证据表明，巨核细胞生成受损在DPR的发生发展中起关键作用。在本研究中，我们报告了DPR患者造血干细胞和巨核细胞祖细胞（MKP）的CG岛存在显著的高甲基化。用去甲基化药物地西他滨治疗可降低MKP中的甲基化CG水平，并增强小鼠巨核细胞的生成。此外，我们发现DNMT3A对源自原代造血干细胞的巨核细胞谱系中的巨核细胞生成具有负调控作用。移植过表达DNMT3A的造血干细胞会阻碍小鼠HSCT后的血小板植入。我们进一步证明，在巨核细胞生成过程中，DNMT3A直接与ETS1和RUNX1结合并使其甲基化。这些发现突出了DPR中异常的DNA甲基化，并表明去甲基化药物可能通过靶向DNMT3A介导的甲基化来改善巨核细胞的增殖和分化。
