Clonal hematopoiesis (CH) is a common condition linked to aging, involving subtle changes within blood-forming stem cells located in the bone marrow. A small number of these stem cells acquire specific genetic mutations. These mutations lead to the expansion of a “clone” of cells, descended from a single mutated ancestor. While not considered a disease itself, CH signifies genetic alterations in the body’s blood production system.
Understanding Clonal Hematopoiesis
Hematopoiesis refers to the continuous process of creating all types of blood cells, including red blood cells, white blood cells, and platelets. It begins with hematopoietic stem cells (HSCs) in the bone marrow, which self-renew and differentiate into specialized blood cells. As individuals age, these HSCs can spontaneously acquire genetic mutations in their DNA.
The term “clonal” means a specific genetic mutation arises in one of these stem cells, giving it a competitive advantage over other healthy stem cells. This allows the mutated cell to divide more efficiently, forming a “clone” of identical blood cells. These mutated cells gradually expand, producing a subpopulation that slowly increases within the body’s overall blood cell population.
Common genetic mutations associated with CH occur in genes such as DNMT3A, TET2, and ASXL1, which regulate gene expression and cell growth. While DNMT3A is the most prevalent driver mutation, TET2 mutations and splicing gene mutations become more common in individuals over 75 years. Clonal expansion is strongly correlated with age, with fewer than 1% of people under 40 affected, but it becomes increasingly common in older adults, affecting approximately 10.4% of individuals over 65 years.
CH often remains asymptomatic. It is distinct from, though it can sometimes precede, overt blood cancers. The presence of these mutated cells at detectable levels, typically with a mutant allele fraction of at least 2%, is often termed clonal hematopoiesis of indeterminate potential (CHIP).
Health Risks Associated with Clonal Hematopoiesis
CH is recognized as a risk factor for several health conditions. There are two primary health concerns linked to the presence of CH. The absolute risk for any individual remains relatively low, but CH elevates the likelihood of developing these conditions.
Individuals with CH have an increased risk of developing myeloid blood cancers, such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). While the annual risk of progressing to blood cancer is generally low (0.5% to 1%), the relative risk can be significantly higher compared to those without CH. For instance, it can be associated with a 10-fold increased risk of hematopoietic malignancy.
Beyond blood cancers, CH is also linked to an elevated risk of cardiovascular disease, including heart attack, stroke, and heart failure. CH can nearly double the cardiovascular risk independent of traditional risk factors. This is mediated by the mutated blood cells, particularly myeloid cells, contributing to chronic inflammation and plaque buildup in arteries, accelerating atherosclerosis.
Chronic inflammation connects CH to these conditions. Mutated cells, particularly those with TET2 mutations, are involved in pro-inflammatory signaling that can accelerate atherosclerosis and contribute to heart failure. While CH increases the risk, it is a risk factor, not a guarantee, and many individuals with CH will not develop these serious diseases.
Detecting Clonal Hematopoiesis
Clonal hematopoiesis typically does not cause noticeable symptoms and is frequently discovered incidentally during medical evaluations. Its identification relies on advanced genetic testing methods that detect specific mutations in blood cells.
The most common technique is next-generation sequencing (NGS). This technology allows detailed analysis of DNA from blood samples, identifying specific genetic mutations, even at low levels. Such testing is not currently part of routine screening for the general population.
Genetic testing for CH is often performed in specific clinical contexts. This includes evaluating individuals with unexplained abnormalities in their blood counts, as part of a workup for suspected blood disorders, or in large-scale research studies. The presence of these mutations, even in a small fraction of blood cells, indicates CH.
Living with Clonal Hematopoiesis
Currently, there is no specific treatment directly targeting clonal hematopoiesis, as it is a risk factor rather than an active disease. Management focuses on monitoring and mitigating the risks of associated health conditions.
Regular medical monitoring and discussions with healthcare providers are important, especially if other risk factors for blood cancers or cardiovascular disease exist. While most individuals with CH have a low risk of developing blood cancer, certain features, such as specific gene mutations like TP53 or spliceosome genes, or a higher proportion of mutated cells, may indicate a greater need for close observation, potentially involving blood tests or bone marrow biopsies.
To reduce the risk of cardiovascular disease, a more common concern with CH, lifestyle modifications are recommended. These include:
Adopting a healthy diet
Engaging in regular physical activity
Maintaining a healthy body weight
Managing conditions such as high blood pressure, high cholesterol, and diabetes
Quitting smoking
Many individuals with CH live long, healthy lives without developing related diseases.