Mutation-dependent responses to sleep and exercise in clonal haematopoiesis

Area of Science:

• Hematology
• Cardiovascular Biology
• Genetics

Background:

• Clonal hematopoiesis (CH) is linked to inflammation and increased atherosclerosis risk.
• The impact of lifestyle factors on CH clone expansion and cellular programming remains largely unknown.

Purpose of the Study:

• To investigate how lifestyle interventions, specifically sleep and exercise, affect CH clone expansion and the development of atherosclerosis.
• To determine if lifestyle interventions selectively reprogram CH mutant cells and associated immune cells.

Main Methods:

• Analysis of human datasets and murine models with various CH-associated mutations (Jak2, Tet2, Trp53, Dnmt3a).
• Assessment of clone expansion, cellular phenotypes, inflammatory signaling (IL-1β, inflammasome), and atherosclerosis.
• Investigation of molecular mechanisms involving noradrenaline and ADRβ2 signaling in macrophages.

Main Results:

• Physical activity correlated with lower non-DNMT3A-driven CH prevalence in humans.
• Sleep and exercise curtailed clone expansion in Jak2^V617F and Tet2 loss-of-function (LOF) CH mouse models.
• Lifestyle interventions selectively reprogrammed mutant hematopoietic progenitor cells and vascular macrophages, reducing inflammation and atherosclerosis.
• Sleep blunted inflammasome activation in Jak2^V617F macrophages, while exercise utilized noradrenaline signaling via ADRβ2 to repress inflammation.

Conclusions:

• Healthy lifestyles, including sleep and exercise, demonstrate gene-specific effects on CH.
• These interventions selectively reprogram mutant hematopoietic progenitor cells and macrophages, offering a novel strategy to mitigate CH-driven atherosclerosis.
• Lifestyle modifications represent a promising approach to maintain cardiovascular health in individuals with CH.