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Clinics in Geriatric Medicine Aug 2019In hematopoiesis, mature blood cells, granulocytes, erythrocytes, and megakaryocytes originate from hematopoietic stem cells. With age, changes in hematopoiesis may have... (Review)
Review
In hematopoiesis, mature blood cells, granulocytes, erythrocytes, and megakaryocytes originate from hematopoietic stem cells. With age, changes in hematopoiesis may have clinical consequences: defective immune responses, cytopenias (most commonly anemia and lymphopenia), hematological malignancy, and effects mediated by hematopoietic cells in other organs. Clonal hematopoiesis is commonly seen with aging and has been associated with both blood concerns and atherosclerosis, but further study is required to determine a causative link.
Topics: Aged; Aging; Anemia; Female; Hematopoiesis; Humans; Male
PubMed: 31230730
DOI: 10.1016/j.cger.2019.03.001 -
Blood Oct 2020Clonal expansions of mutated hematopoietic cells, termed clonal hematopoiesis, are common in aging humans. One expected consequence of mutation-associated clonal... (Review)
Review
Clonal expansions of mutated hematopoietic cells, termed clonal hematopoiesis, are common in aging humans. One expected consequence of mutation-associated clonal hematopoiesis is an increased risk of hematologic cancers, which has now been shown in several studies. However, the hematopoietic stem cells that acquire these somatic mutations also give rise to mutated immune effector cells, such as monocytes, granulocytes, and lymphocytes. These effector cells can potentially influence many disease states, especially those with a chronic inflammatory component. Indeed, several studies have now shown that clonal hematopoiesis associates with increased risk of atherosclerotic cardiovascular disease. Emerging data also associate clonal hematopoiesis with other nonhematologic diseases. Here, we will review recent studies linking clonal hematopoiesis to altered immune function, inflammation, and nonmalignant diseases of aging.
Topics: Animals; Biomarkers; Cardiovascular Diseases; Clonal Evolution; Clonal Hematopoiesis; Disease Susceptibility; Genetic Association Studies; Genetic Predisposition to Disease; Hematopoiesis; Humans; Mutation; Organ Specificity; Phenotype; Terminology as Topic
PubMed: 32736379
DOI: 10.1182/blood.2019000989 -
Annual Review of Pathology Jan 2020Traditional risk factors are incompletely predictive of cardiovascular disease development, a leading cause of death in the elderly. Recent epidemiological studies have... (Review)
Review
Traditional risk factors are incompletely predictive of cardiovascular disease development, a leading cause of death in the elderly. Recent epidemiological studies have shown that human aging is associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive advantage to a mutant cell, thus allowing for its clonal expansion, a phenomenon known as clonal hematopoiesis. Unexpectedly, these mutations have been associated with a higher incidence of cardiovascular disease, suggesting a previously unrecognized connection between somatic mutations in hematopoietic cells and cardiovascular disease. Here, we provide an up-to-date review of clonal hematopoiesis and its association with aging and cardiovascular disease. We also give a detailed report of the experimental studies that have been instrumental in understanding the relationship between clonal hematopoiesis and cardiovascular disease and have shed light on the mechanisms by which hematopoietic somatic mutations contribute to disease pathology.
Topics: Aged; Aged, 80 and over; Aging; Cardiovascular Diseases; Cells, Cultured; Clonal Evolution; Hematopoiesis; Humans; Incidence; Mutation; Risk Factors
PubMed: 31689371
DOI: 10.1146/annurev-pathmechdis-012419-032544 -
Nature Jan 2018The development of mature blood cells from haematopoietic stem cells has long served as a model for stem-cell research, with the haematopoietic differentiation tree... (Review)
Review
The development of mature blood cells from haematopoietic stem cells has long served as a model for stem-cell research, with the haematopoietic differentiation tree being widely used as a model for the maintenance of hierarchically organized tissues. Recent results and new technologies have challenged the demarcations between stem and progenitor cell populations, the timing of cell-fate choices and the contribution of stem and multipotent progenitor cells to the maintenance of steady-state blood production. These evolving views of haematopoiesis have broad implications for our understanding of the functions of adult stem cells, as well as the development of new therapies for malignant and non-malignant haematopoietic diseases.
Topics: Adult Stem Cells; Animals; Cell Cycle; Cell Lineage; Cell Self Renewal; Gene Expression Profiling; Hematologic Diseases; Hematopoiesis; Hematopoietic Stem Cells; Humans; Multipotent Stem Cells; Single-Cell Analysis
PubMed: 29364285
DOI: 10.1038/nature25022 -
Physiological Reviews Jan 2023Somatic mosaicism, the occurrence of multiple genetically distinct cell clones within the same tissue, is an evitable consequence of human aging. The hematopoietic... (Review)
Review
Somatic mosaicism, the occurrence of multiple genetically distinct cell clones within the same tissue, is an evitable consequence of human aging. The hematopoietic system is no exception to this, where studies have revealed the presence of expanded blood cell clones carrying mutations in preleukemic driver genes and/or genetic alterations in chromosomes. This phenomenon is referred to as clonal hematopoiesis and is remarkably prevalent in elderly individuals. While clonal hematopoiesis represents an early step toward a hematological malignancy, most individuals will never develop blood cancer. Somewhat unexpectedly, epidemiological studies have found that clonal hematopoiesis is associated with an increase in the risk of all-cause mortality and age-related disease, particularly in the cardiovascular system. Studies using murine models of clonal hematopoiesis have begun to shed light on this relationship, suggesting that driver mutations in mature blood cells can causally contribute to aging and disease by augmenting inflammatory processes. Here we provide an up-to-date review of clonal hematopoiesis within the context of somatic mosaicism and aging and describe recent epidemiological studies that have reported associations with age-related disease. We will also discuss the experimental studies that have provided important mechanistic insight into how driver mutations promote age-related disease and how this knowledge could be leveraged to treat individuals with clonal hematopoiesis.
Topics: Humans; Mice; Animals; Aged; Hematopoiesis; Clonal Hematopoiesis; Hematopoietic Stem Cells; Mosaicism; Cardiovascular Diseases; Mutation
PubMed: 36049115
DOI: 10.1152/physrev.00004.2022 -
Annual Review of Medicine Jan 2023Aging is associated with increased mutational burden in every tissue studied. Occasionally, fitness-increasing mutations will arise, leading to stem cell clonal... (Review)
Review
Aging is associated with increased mutational burden in every tissue studied. Occasionally, fitness-increasing mutations will arise, leading to stem cell clonal expansion. This process occurs in several tissues but has been best studied in blood. Clonal hematopoiesis is associated with an increased risk of blood cancers, such as acute myeloid leukemia, which result if additional cooperating mutations occur. Surprisingly, it is also associated with an increased risk of nonmalignant diseases, such as atherosclerotic cardiovascular disease. This may be due to enhanced inflammation in mutated innate immune cells, which could be targeted clinically with anti-inflammatory drugs. Recent studies have uncovered other factors that predict poor outcomes in patients with clonal hematopoiesis, such as size of the mutant clone, mutated driver genes, and epigenetic aging. Though clonality is inevitable and largely a function of time, recent work has shown that inherited genetic variation can also influence this process. Clonal hematopoiesis provides a paradigm for understanding how age-related changes in tissue stem cell composition and function influence human health.
Topics: Humans; Clonal Hematopoiesis; Hematopoiesis; Hematologic Neoplasms; Aging; Precancerous Conditions; Mutation
PubMed: 36450282
DOI: 10.1146/annurev-med-042921-112347 -
Cells Mar 2023The haematopoietic system plays an essential role in our health and survival. It is comprised of a range of mature blood and immune cell types, including oxygen-carrying... (Review)
Review
The haematopoietic system plays an essential role in our health and survival. It is comprised of a range of mature blood and immune cell types, including oxygen-carrying erythrocytes, platelet-producing megakaryocytes and infection-fighting myeloid and lymphoid cells. Self-renewing multipotent haematopoietic stem cells (HSCs) and a range of intermediate haematopoietic progenitor cell types differentiate into these mature cell types to continuously support haematopoietic system homeostasis throughout life. This process of haematopoiesis is tightly regulated in vivo and primarily takes place in the bone marrow. Over the years, a range of in vitro culture systems have been developed, either to expand haematopoietic stem and progenitor cells or to differentiate them into the various haematopoietic lineages, based on the use of recombinant cytokines, co-culture systems and/or small molecules. These approaches provide important tractable models to study human haematopoiesis in vitro. Additionally, haematopoietic cell culture systems are being developed and clinical tested as a source of cell products for transplantation and transfusion medicine. This review discusses the in vitro culture protocols for human HSC expansion and differentiation, and summarises the key factors involved in these biological processes.
Topics: Humans; Hematopoietic Stem Cells; Cell Differentiation; Megakaryocytes; Hematopoiesis; Bone Marrow
PubMed: 36980237
DOI: 10.3390/cells12060896 -
Cell Stem Cell Jun 2022Clonal hematopoiesis of indeterminate potential (CHIP) describes a widespread expansion of genetically variant hematopoietic cells that increases exponentially with age... (Review)
Review
Clonal hematopoiesis of indeterminate potential (CHIP) describes a widespread expansion of genetically variant hematopoietic cells that increases exponentially with age and is associated with increased risks of cancers, cardiovascular disease, and other maladies. Here, we discuss how environmental contexts associated with CHIP, such as old age, infections, chemotherapy, or cigarette smoking, alter tissue microenvironments to facilitate the selection and expansion of specific CHIP mutant clones. Further, we consider major remaining gaps in knowledge, including intrinsic effects, clone size thresholds, and factors affecting clonal competition, that will determine future application of this field in transplant and preventive medicine.
Topics: Clonal Hematopoiesis; Hematopoiesis; Hematopoietic Stem Cells; Mutation; Risk Factors
PubMed: 35659875
DOI: 10.1016/j.stem.2022.05.006 -
Annual Review of Pathology Jan 2024Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been... (Review)
Review
Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond.
Topics: Humans; Clonal Hematopoiesis; Hematologic Neoplasms; Myelodysplastic Syndromes; Aging; Inflammation; Hematopoiesis
PubMed: 37832948
DOI: 10.1146/annurev-pathmechdis-051222-122724 -
Journal of Clinical Oncology : Official... Mar 2023To prospectively examine the association between clonal hematopoiesis (CH) and subsequent risk of lung cancer.
PURPOSE
To prospectively examine the association between clonal hematopoiesis (CH) and subsequent risk of lung cancer.
METHODS
Among 200,629 UK Biobank (UKBB) participants with whole-exome sequencing, CH was identified in a nested case-control study of 832 incident lung cancer cases and 3,951 controls (2006-2019) matched on age and year at blood draw, sex, race, and smoking status. A similar nested case-control study (141 cases/652 controls) was conducted among 27,975 participants with whole-exome sequencing in the Mass General Brigham Biobank (MGBB, 2010-2021). In parallel, we compared CH frequency in published data from 5,003 patients with solid tumor (2,279 lung cancer) who had pretreatment blood sequencing performed through Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets.
RESULTS
In UKBB, the presence of CH was associated with increased risk of lung cancer (cases: 12.5% controls: 8.7%; multivariable-adjusted odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74). The association remained robust after excluding participants with chronic obstructive pulmonary disease. No significant interactions with known risk factors, including polygenic risk score and C-reactive protein, were identified. In MGBB, we observed similar enrichment of CH in lung cancer (cases: 15.6% controls: 12.7%). The meta-analyzed OR (95% CI) of UKBB and MGBB was 1.35 (1.08 to 1.68) for CH overall and 1.61 (1.19 to 2.18) for variant allele frequencies ≥ 10%. In Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, CH with a variant allele frequency ≥ 10% was enriched in pretreatment lung cancer compared with other tumors after adjusting for age, sex, and smoking (OR for lung breast cancer: 1.61; 95% CI, 1.03 to 2.53).
CONCLUSION
Independent of known risk factors, CH is associated with increased risk of lung cancer.
Topics: Humans; Clonal Hematopoiesis; Case-Control Studies; Hematopoiesis; Lung Neoplasms; Mutation; Risk Factors
PubMed: 36480766
DOI: 10.1200/JCO.22.00857