Biomaterial Database

Obesity-induced inflammation exacerbates clonal hematopoiesis. 2023

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

Herman B Wells Center for Pediatric Research, Department of Pediatrics and.

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.

UI	MeSH Term	Description	Entries
D007249	Inflammation	A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.	Innate Inflammatory Response,Inflammations,Inflammatory Response, Innate,Innate Inflammatory Responses
D009154	Mutation	Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.	Mutations
D009765	Obesity	A status with BODY WEIGHT that is grossly above the recommended standards, usually due to accumulation of excess FATS in the body. The standards may vary with age, sex, genetic or cultural background. In the BODY MASS INDEX, a BMI greater than 30.0 kg/m2 is considered obese, and a BMI greater than 40.0 kg/m2 is considered morbidly obese (MORBID OBESITY).
D006410	Hematopoiesis	The development and formation of various types of BLOOD CELLS. Hematopoiesis can take place in the BONE MARROW (medullary) or outside the bone marrow (HEMATOPOIESIS, EXTRAMEDULLARY).	Hematopoiesis, Medullary,Haematopoiesis,Medullary Hematopoiesis
D006412	Hematopoietic Stem Cells	Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood.	Colony-Forming Units, Hematopoietic,Progenitor Cells, Hematopoietic,Stem Cells, Hematopoietic,Hematopoietic Progenitor Cells,Cell, Hematopoietic Progenitor,Cell, Hematopoietic Stem,Cells, Hematopoietic Progenitor,Cells, Hematopoietic Stem,Colony Forming Units, Hematopoietic,Colony-Forming Unit, Hematopoietic,Hematopoietic Colony-Forming Unit,Hematopoietic Colony-Forming Units,Hematopoietic Progenitor Cell,Hematopoietic Stem Cell,Progenitor Cell, Hematopoietic,Stem Cell, Hematopoietic,Unit, Hematopoietic Colony-Forming,Units, Hematopoietic Colony-Forming
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000082182	Clonal Hematopoiesis	Expansion of blood cells arising from mutant HEMATOPOIETIC STEM CELLS often related to aging. Mutations on epigenetic regulator genes are common in clonal hematopoiesis and may be a risk factor for HEMATOLOGIC NEOPLASMS and other cardiovascular diseases. When variant allele fraction is at least 2% and is present in the absence of severe cytopenias it is referred to as clonal hematopoiesis of indeterminate potential (CHIP).	ARCH Age-related Clonal Hematopoiesis,Age-related Clonal Hematopoiesis,CCUS Clonal Cytopenia of Undetermined Significance,CHIP Clonal Hematopoiesis of Indeterminate Potential,Clonal Cytopenia of Undetermined Significance,Clonal Hematopoiesis of Indeterminate Potential,ICUS Idiopathic Cytopenias of Undetermined Significance,Idiopathic Cytopenias of Undetermined Significance,ARCH Age related Clonal Hematopoiesis,Age related Clonal Hematopoiesis,Clonal Hematopoiesis, Age-related,Hematopoiesis, Age-related Clonal,Hematopoiesis, Clonal
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D019337	Hematologic Neoplasms	Neoplasms located in the blood and blood-forming tissue (the bone marrow and lymphatic tissue). The commonest forms are the various types of LEUKEMIA, of LYMPHOMA, and of the progressive, life-threatening forms of the MYELODYSPLASTIC SYNDROMES.	Blood Cancer,Hematologic Malignancies,Hematopoietic Neoplasms,Hematologic Malignancy,Hematological Malignancies,Hematological Neoplasms,Hematopoietic Malignancies,Malignancies, Hematologic,Malignancy, Hematologic,Neoplasms, Hematologic,Neoplasms, Hematopoietic,Blood Cancers,Cancer, Blood,Hematologic Neoplasm,Hematological Malignancy,Hematological Neoplasm,Hematopoietic Malignancy,Hematopoietic Neoplasm,Malignancy, Hematological,Malignancy, Hematopoietic,Neoplasm, Hematologic,Neoplasm, Hematological,Neoplasm, Hematopoietic