Obesity-induced inflammation exacerbates clonal hematopoiesis

Abstract

Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis (CH) of indeterminate potential (CHIP) is frequent in ageing, involves expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, risk factors that contribute to CHIP-associated CH are poorly understood. Obesity induces a pro-inflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data from 47,466 individuals with validated CHIP in UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1 and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and a pro-inflammatory state can potentiate progression of CHIP to more significant hematologic neoplasia. Calcium channel blocker, nifedipine or SKF-96365, either alone or in combination with metformin, MCC950 or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in obese individuals.

Clonal Hematopoiesis of Indeterminate Potential With Loss of Tet2 Enhances Risk for Atrial Fibrillation Through Nlrp3 Inflammasome Activation

“…Growing evidence suggests chronic low-grade inflammation associated with aging contributes substantially to agerelated disorders, including CVD and AF. [56][57][58] It is notable that mice and humans with TET2-mutant CHIP have 3,15,22,59 Previous studies highlight the importance of cardiomyocyte NLPR3 inflammasome activation and IL-1β in the pathogenesis of AF and atherosclerotic burden. 4,9,30,[52][53][54] We found that heightened susceptibility to AF in our mouse model depends on the Nlrp3 inflammasome, whose expression is markedly increased by hematopoietic-specific Tet2 deficiency.…”

Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche

“…Adipocytes have been shown to impair B cell differentiation of HSCs and adipocyte numbers in aged individuals correlate with an increased density of maturing myeloid cells adjacent to adipocytes, suggesting that the age-related skewing of MSCs into the adipogenic lineage may contribute to myeloid skewing of HSCs [ 68 , 69 ]. Adipocytes produce proinflammatory cytokines, which may facilitate the inflammatory microenvironment in aged BM and thereby exacerbate CH [ 70 , 71 ]. Conversely, the reduced osteogenic differentiation of MSCs, which is associated with lower production of osteopontin (OPN), may negatively regulate HSC proliferation, and thus lead to accelerated HSC divisions and stem cell exhaustion during aging [ 72 ].…”

Mutations, inflammation and phenotype of myeloproliferative neoplasms

“…The influence of dietary factors on the risk of MPN has been investigated: the only finding was that a high intake of caffeine protects against PV ( 107 ). In contrast, obesity elevates the risk for clonal hematopoiesis and MPN, especially ET ( 108 , 109 ). A high-fat diet predisposes to chronic inflammation, leukocytosis and thrombocytosis, whereas adherence to a Mediterranean diet has been shown to reduce symptoms in MPN patients ( 107 – 110 ).…”