Invited Speaker 3rd Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity 2022

The dysfunctional metabolism in diabetes and obesity dysregulates the TET2-AMPK axis and accelerates DNMT3A clonal haematopoiesis (#37)

Andrew Murphy 1 2 3 , Camilla Bertuzzo Veiga 1 4 , Dragana Dragoljevic 1 2 3 , Pooranee K Morgan 1 , Andrew J Fleetwood 1 2 , Marco Herold 5 , Matthew Watt 4 , Man K.S. Lee 1 2 3
  1. Baker IDI Heart and Diabetes Institute, St Kilda Road Central, VIC, Australia
  2. Baker Heart and Diabetes Institute, St Kilda Road Central, VIC, Australia
  3. Department of Immunology, Monash University, Melbourne
  4. Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia
  5. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

Somatic mutations in haematopoietic stem cells (HSCs) are almost ubiquitous in people over 50 years of age. Expansion of a mutated HSC can result in blood disorders termed Clonal haematopoiesis of indeterminate potential (CHIP). People with CHIP have an increased risk of cardiovascular mortality and the prevalence of CHIP is increased with diabetes. DNMT3A and TET2 are commonly mutated in CHIP. AMPK directly phosphorylates and thereby activates TET2, which is reduced in diabetes. We hypothesise that hyperglycaemia induces TET2 dysfunction in HSCs via AMPK downregulation, which in the presence of DNMT3Amutant-CHIP, accelerates clonal outgrowth. In vitro and two murine models of DNMT3Amutant-CHIP, hyperglycaemia induce TET2 dysfunction in HSCs and accelerated DNMT3Amutant clonal outgrowth towards myeloid cells. Administration of an AMPK activator (O-304) reversed these effects. Additionally, obese DNMT3Amutant-CHIP mice were found to have enhanced clonal outgrowth with also more susceptible to metabolic complications and presented with DNMT3Amutant-myeloid cells infiltrating in several tissues. Together, our data reveals how metabolic disorders accelerates CHIP through AMPK.