 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Feb 06, 2025 |
| Title |
Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk. 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-HSCs. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank 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 that modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.
|
| |
|
| Overall design |
HSPCs were extracted from two primaryDnmt3R882H/+mice and used for the CRISPR screen.
|
| |
|
| Contributor(s) |
Gozdecka M, Dudek M, Wen S, Fabre MA, Rak J, Gu M, Damaskou A, Huntly BJ, Vassiliou GS |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Feb 27, 2024 |
| Last update date |
Feb 06, 2025 |
| Contact name |
Muxin Gu |
| E-mail(s) |
muxingu@gmail.com, mg445@cam.ac.uk
|
| Phone |
01223767800
|
| Organization name |
University of Cambridge
|
| Department |
Haematology
|
| Lab |
George Vassiliou
|
| Street address |
Jeffrey Cheah Biomedical Centre, Puddicombe Way
|
| City |
Cambridge |
| ZIP/Postal code |
CB2 0AW |
| Country |
United Kingdom |
| |
|
| Platforms (1) |
|
| Samples (12)
|
|
| Relations |
| BioProject |
PRJNA1081425 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE259404_count_table.txt.gz |
3.2 Mb |
(ftp)(http) |
TXT |
| GSE259404_day10.gene_summary.txt.gz |
563.7 Kb |
(ftp)(http) |
TXT |
| GSE259404_day10.sgrna_summary.txt.gz |
5.3 Mb |
(ftp)(http) |
TXT |
| GSE259404_day15.gene_summary.txt.gz |
562.8 Kb |
(ftp)(http) |
TXT |
| GSE259404_day15.sgrna_summary.txt.gz |
5.3 Mb |
(ftp)(http) |
TXT |
| GSE259404_day20.gene_summary.txt.gz |
565.1 Kb |
(ftp)(http) |
TXT |
| GSE259404_day20.sgrna_summary.txt.gz |
5.3 Mb |
(ftp)(http) |
TXT |
| GSE259404_day25.gene_summary.txt.gz |
564.3 Kb |
(ftp)(http) |
TXT |
| GSE259404_day25.sgrna_summary.txt.gz |
5.3 Mb |
(ftp)(http) |
TXT |
| GSE259404_day30.gene_summary.txt.gz |
564.6 Kb |
(ftp)(http) |
TXT |
| GSE259404_day30.sgrna_summary.txt.gz |
5.3 Mb |
(ftp)(http) |
TXT |
| GSE259404_day6.gene_summary.txt.gz |
560.0 Kb |
(ftp)(http) |
TXT |
| GSE259404_day6.sgrna_summary.txt.gz |
5.3 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
|
|
|
|
 |
Less...
More...