AI Article Synopsis

  • *The most common mutation causing CH is found in a gene called DNA methyltransferase 3 alpha, specifically at a spot called R882.
  • *Researchers found that a drug called metformin can slow down the growth of these mutated blood cells and may help prevent illnesses related to CH in people.

Article Abstract

Clonal hematopoiesis (CH) arises when a hematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type (WT) HSCs, resulting in its clonal expansion. Individuals with CH are at an increased risk of developing hematologic neoplasms and a range of age-related inflammatory illnesses. Therapeutic interventions that suppress the expansion of mutant HSCs have the potential to prevent these CH-related illnesses; however, such interventions have not yet been identified. The most common CH driver mutations are in the DNA methyltransferase 3 alpha () gene with arginine 882 (R882) being a mutation hotspot. Here we show that murine hematopoietic stem and progenitor cells (HSPCs) carrying the mutation, which is equivalent to human , have increased mitochondrial respiration compared with WT cells and are dependent on this metabolic reprogramming for their competitive advantage. Importantly, treatment with metformin, an oral anti-diabetic drug with inhibitory activity against complex I in the electron transport chain (ETC), reduced the fitness of HSCs. Through a multi-omics approach, we discovered that metformin acts by enhancing the methylation potential in HSPCs and reversing their aberrant DNA CpG methylation and histone H3K27 trimethylation (H3K27me3) profiles. Metformin also reduced the fitness of human HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against illnesses associated with mutation-driven CH in humans.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10889081PMC
http://dx.doi.org/10.21203/rs.3.rs-3874821/v1DOI Listing

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