Obesity-induced inflammation exacerbates clonal hematopoiesis
Santhosh Kumar Pasupuleti, … , Pradeep Natarajan, Reuben Kapur
Santhosh Kumar Pasupuleti, … , Pradeep Natarajan, Reuben Kapur
Published April 18, 2023
Citation Information: J Clin Invest. 2023;133(11):e163968. https://doi.org/10.1172/JCI163968.
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Research Article Hematology Inflammation

Obesity-induced inflammation exacerbates clonal hematopoiesis

Abstract

Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis of indeterminate potential (CHIP) is frequent in aging and involves the expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, the risk factors that contribute to CHIP-associated clonal hematopoiesis (CH) are poorly understood. Obesity induces a proinflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data for 47,466 individuals with validated CHIP in the UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in the 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 that a proinflammatory state could potentiate the progression of CHIP to more significant hematologic neoplasia. The calcium channel blockers nifedipine and 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 individuals with obesity.

Authors

Santhosh Kumar Pasupuleti, Baskar Ramdas, Sarah S. Burns, Lakshmi Reddy Palam, Rahul Kanumuri, Ramesh Kumar, Taruni Reddy Pandhiri, Utpal P. Dave, Nanda Kumar Yellapu, Xinyu Zhou, Chi Zhang, George E. Sandusky, Zhi Yu, Michael C. Honigberg, Alexander G. Bick, Gabriel K. Griffin, Abhishek Niroula, Benjamin L. Ebert, Sophie Paczesny, Pradeep Natarajan, Reuben Kapur

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Figure 6

The Ca2+ signaling pathway is enriched in Ob/Ob mice bearing Tet2–/– cells.

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The Ca2+ signaling pathway is enriched in Ob/Ob mice bearing Tet2–/– cel...
(A) Heatmap of the expression of calcium channel–related genes in obese and WT mice bearing Tet2–/– cells. (B) WB analysis was performed to measure the protein levels of Nfatc3, Irg1, and IL-1β in BM cells from Tet2–/– Ob/Ob, Tet2–/–, Ob/Ob, and WT mice. (C) Expression of the Nfatc3 gene in Tet2–/– Ob/Ob compound mutant mice and control mice BM cells was detected by qRT-PCR. (D) HSC/Ps from Tet2–/– Ob/Ob, Tet2–/–, Ob/Ob, and WT mice were stimulated or not with 1 μm ionomycin, and Nfatc3 (green) localization was visualized by confocal microscopy. DAPI (red, pseudocolor) was used to stain the nucleus. Red arrow indicate nuclear translocation of Nfat3. Scale bars: 10 μM . The insets show the zoomed images (×2). (E and F) Quantification of the percentage of cells with nuclear Nfatc3 per high-power field using Fiji (ImageJ, NIH). (G) GSEA plot of gene sets related to the Ca2+/calcineurin-activated NFAT pathway that were upregulated in Ob/Ob mice bearing Tet2–/– cells compared with WT mice. NES, normalized enrichment score Data are shown as the mean ± SEM. *P < 0.05, **P < 0.005, ***P < 0.0005, and ****P < 0.0001, by 1-way ANOVA.