二甲双胍降低了Dnmt3aR878H HSPC竞争优势，这一成果由加拿大玛嘉烈公主癌症中心Steven M. Chan团队经过不懈努力而取得。相关论文于2025年4月16日发表在《自然》杂志上。

本研究表明，携带Dnmt3a^R878H/+突变（相当于人类DNMT3A^R882H/+）的小鼠造血干细胞和祖细胞（HSPCs）与野生型细胞相比，线粒体呼吸增加，并依赖于这种代谢重编程来获得竞争优势。二甲双胍（一种抑制线粒体呼吸的抗糖尿病药物）治疗降低了Dnmt3a^R878H/+造血干细胞的竞争优势。通过多组学方法，该课题组人员发现二甲双胍通过增强Dnmt3a^R878H/+ HSPCs的甲基化电位，逆转这些细胞中异常的DNA CpG甲基化和组蛋白H3 K27三甲基化谱起作用。二甲双胍还降低了通过启动编辑生成的人类DNMT3AR882H HSPCs的竞争优势。他们的发现为研究二甲双胍作为预防人类DNMT3A R882突变驱动的克隆造血的预防性干预提供了临床前依据。

研究人员表示，当造血干细胞（HSC）获得一种突变，使其比野生型HSC具有竞争优势，从而导致其克隆扩增时，就会出现克隆造血。克隆造血个体发生血液病肿瘤和其他年龄相关炎症性疾病的风险增加。抑制突变hsc的扩增可能会阻止这些结果；然而，这些干预措施尚未确定。最常见的克隆造血驱动突变是DNMT3A基因，其中精氨酸882 （R882）是突变热点。

附：英文原文

Title: Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs

Author: Hosseini, Mohsen, Voisin, Veronique, Chegini, Ali, Varesi, Angelica, Cathelin, Severine, Ayyathan, Dhanoop Manikoth, Liu, Alex C. H., Yang, Yitong, Wang, Vivian, Maher, Abdula, Grignano, Eric, Reisz, Julie A., DAlessandro, Angelo, Young, Kira, Wu, Yiyan, Fiumara, Martina, Ferrari, Samuele, Naldini, Luigi, Gaiti, Federico, Pai, Shraddha, Egan, Grace, Schimmer, Aaron D., Bader, Gary D., Dick, John E., Xie, Stephanie Z., Trowbridge, Jennifer J., Chan, Steven M.

Issue&Volume: 2025-04-16

Abstract: Clonal haematopoiesis arises when a haematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type HSCs, resulting in its clonal expansion. Individuals with clonal haematopoiesis are at increased risk of developing haematologic neoplasms and other age-related inflammatory illnesses1,2,3,4. Suppressing the expansion of mutant HSCs may prevent these outcomes; however, such interventions have not yet been identified. The most common clonal haematopoiesis driver mutations are in the DNMT3A gene, with arginine 882 (R882) being a mutation hotspot1,2,3,5,6,7. Here we show that mouse haematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with wild-type cells and are dependent on this metabolic reprogramming for their competitive advantage. Treatment with metformin, an anti-diabetic drug that inhibits mitochondrial respiration8, reduced the competitive advantage of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we found that metformin acts by enhancing methylation potential in Dnmt3aR878H/+ HSPCs and reversing the aberrant DNA CpG methylation and histone H3 K27 trimethylation profiles in these cells. Metformin also reduced the competitive advantage of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against DNMT3A R882 mutation-driven clonal haematopoiesis in humans.

DOI: 10.1038/s41586-025-08871-w

Source: https://www.nature.com/articles/s41586-025-08871-w