| Title: | Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis |
| Journal: | Nature |
| Published: | 16 Apr 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40239706/ |
| DOI: | https://doi.org/10.1038/s41586-025-08980-6 |
Publication 15812
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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. Among the 640 vulnerability genes identified, many were involved in mitochondrial metabolism, and metabolic flux analysis confirmed enhanced oxidative phosphorylation use in Dnmt3aR882H/+ versus 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, long-term haematopoietic stem cells. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank participants showed that individuals taking metformin had a 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.</p>
16 Keywords
- Animals
- Clonal Hematopoiesis
- Clone Cells
- DNA (Cytosine-5-)-Methyltransferases
- DNA Methyltransferase 3A
- Electron Transport Complex I
- Female
- Hematopoietic Stem Cells
- Humans
- Leukemia, Myeloid, Acute
- Male
- Metformin
- Mice
- Mitochondria
- Mutation
- Oxidative Phosphorylation
42 Authors
- Malgorzata Gozdecka
- Monika Dudek
- Sean Wen
- Muxin Gu
- Richard J. Stopforth
- Justyna Rak
- Aristi Damaskou
- Guinevere L. Grice
- Matthew A. McLoughlin
- Laura Bond
- Rachael Wilson
- George Giotopoulos
- Vijaya Mahalingam Shanmugiah
- Rula Bany Bakar
- Eliza Yankova
- Jonathan L. Cooper
- Nisha Narayan
- Sarah J. Horton
- Ryan Asby
- Dean C. Pask
- Annalisa Mupo
- Graham Duddy
- Ludovica Marando
- Theodoros Georgomanolis
- Paul Carter
- Amirtha Priya Ramesh
- William G. Dunn
- Clea Barcena
- Paolo Gallipoli
- Kosuke Yusa
- Slavé Petrovski
- Penny Wright
- Pedro M. Quiros
- Christian Frezza
- James A. Nathan
- Arthur Kaser
- Siddhartha Kar
- Konstantinos Tzelepis
- Jonathan Mitchell
- Margarete A. Fabre
- Brian J. P. Huntly
- George S. Vassiliou
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