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

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-05-07 DOI:10.1126/sciadv.ads3630

Yaqiong Tang, Xiaofei Song, Ziyan Zhang, Yifang Yao, Tingting Pan, Jiaqian Qi, Lijun Xia, Depei Wu, Yue Han

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Abstract

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.

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DNA的高甲基化损害了异基因造血干细胞移植后延迟血小板恢复的巨核发生

血小板延迟恢复（DPR）是造血干细胞移植（HSCT）常见且复杂的并发症，其机制尚不清楚，患者预后较差。新出现的证据表明，受损的巨核发生在DPR的发展中起着关键作用。在这项研究中，我们报道了DPR患者造血干细胞和巨核细胞祖细胞（MKPs）的CG岛中显著的高甲基化。用低甲基化剂地西他滨治疗可降低MKPs中甲基化CG水平，并增强小鼠巨核细胞的产生。此外，我们发现DNMT3A负调控来自原代造血干细胞的巨核细胞谱系的巨核发生。造血干细胞过表达DNMT3A的移植会阻碍小鼠造血干细胞移植后血小板的植入。我们进一步证明DNMT3A在巨核发生过程中直接结合并甲基化ETS1和RUNX1。这些发现强调了DPR中异常的DNA甲基化，并表明低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。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.