线粒体代谢维持DNMT3A-R882突变克隆造血，这一成果由剑桥大学George S. Vassiliou研究组经过不懈努力而取得。2025年4月16日，国际知名学术期刊《自然》发表了这一成果。

为了确定DNMT3A R882突变特异性漏洞，研究团队对原发性小鼠Dnmt3a^R882H/+ HSPCs进行了全基因组CRISPR筛选。在所鉴定的640个易感基因中，许多与线粒体代谢有关，代谢通量分析证实Dnmt3a^R882H/+与Dnmt3a+/+ (WT) HSPCs中氧化磷酸化水平增强。该研究团队选择了柠檬酸/苹果酸转运体Slc25a1和复合物I组分Ndufb11进行下游研究，这些药物抑制剂是可用的。体内给药SLC25A1抑制剂CTPI2、复合物I抑制剂IACS-010759和二甲双胍可抑制Dnmt3a^R882H/+移植后克隆扩增，但对WT、LT-HSC无抑制作用。二甲双胍的作用在人DNMT3A-R882 CH初级样本中得到了重现。值得注意的是，对412,234名英国生物银行（UKB）参与者的分析显示，在控制了潜在的混杂因素（包括糖化血红蛋白、糖尿病和体重指数）后，服用二甲双胍的个体DNMT3A R882突变CH的患病率明显较低。总的来说，他们的数据提出了线粒体代谢调节作为预防DNMT3A R882突变AML的治疗策略。

据了解，体细胞DNMT3A R882密码子突变驱动最常见的克隆造血（CH）形式，并与急性髓性白血病（AML）风险增加相关。因此，阻止DNMT3A R882突变的造血干细胞/祖细胞（HSPCs）的扩增可能会避免AML的进展。

附：英文原文

Title: Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

Author: Gozdecka, Malgorzata, Dudek, Monika, Wen, Sean, Gu, Muxin, Stopforth, Richard J., Rak, Justyna, Damaskou, Aristi, Grice, Guinevere L., McLoughlin, Matthew A., Bond, Laura, Wilson, Rachael, Giotopoulos, George, Mahalingam Shanmugiah, Vijaya, Bakar, Rula Bany, Yankova, Eliza, Cooper, Jonathan L., Narayan, Nisha, Horton, Sarah J., Asby, Ryan, Pask, Dean C., Mupo, Annalisa, Duddy, Graham, Marando, Ludovica, Georgomanolis, Theodoros, Carter, Paul, Ramesh, Amirtha Priya, Dunn, William G., Barcena, Clea, Gallipoli, Paolo, Yusa, Kosuke, Petrovski, Slav, Wright, Penny, Quiros, Pedro M., Frezza, Christian, Nathan, James A., Kaser, Arthur, Kar, Siddhartha, Tzelepis, Konstantinos, Mitchell, Jonathan, Fabre, Margarete A., Huntly, Brian J. P., Vassiliou, George S.

Issue&Volume: 2025-04-16

Abstract: Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3aR882H/+ HSPCs. Amongst the 640 vulnerability genes identified, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSC. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank (UKB) participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.

DOI: 10.1038/s41586-025-08980-6

Source: https://www.nature.com/articles/s41586-025-08980-6