Mouse study suggests a common diabetes drug may prevent leukaemia

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"... Thanks to recent advances, individuals at high risk of AML [acute myeloid leukaemia] can be identified years in advance using blood tests and blood DNA analysis, but there’s no suitable treatment that can prevent them from developing the disease.

In this study ... investigated how to prevent abnormal blood stem cells with genetic changes from progressing to become AML. The work focused on the most common genetic change, which affects a gene called DNMT3A and is responsible for starting 10-15% of AML cases. ...

The research team examined blood stem cells from mice with the same changes in DNMT3A as seen in the pre-cancerous cells in humans. Using a genome-wide screening technique, they showed that these cells depend more on mitochondrial metabolism than healthy cells, making this a potential weak spot. The researchers went on to confirm that metformin, and other mitochondria-targeting drugs, substantially slowed the growth of mutation-bearing blood cells in mice. Further experiments also showed that metformin could have the same effect on human blood cells with the DNMT3A mutation. ..."

From the abstract:

"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-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."

Mouse study suggests a common diabetes drug may prevent leukaemia | University of Cambridge "Metformin, a widely used and affordable diabetes drug, could prevent a form of acute myeloid leukaemia in people at high risk of the disease, a study in mice has suggested. Further research in clinical trials will be needed to confirm this works for patients."

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis (no public access)