Clonal Hematopoiesis, Clonal Hematopoiesis of Indeterminate Potential, and Age-Related Clonal Hematopoiesis
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P202-203
2025-11-26
69
In the 1960s, it was established that X chromosomal inactivation (XCI) is a random process that takes place at the early female embryonic developmental stages. Since the same X chromosome remains inactive upon multiple cell divisions, XCI analysis allows for low resolution clonal tracking. As hematological malignancies arise from single clones, clonal tracking is a powerful tool that allows for disease monitoring and understanding.
Only recently, high-resolution clonality analyses of healthy individuals without malignant transformation demonstrated two remark able features. First, mature blood cells from these individuals showed imbalanced clonality, suggesting that some HSC clones produced more mature blood cells than others, resulting in their progeny being overrepresented. This is referred to as (oligo-) clonal hematopoiesis. Second, when assessing the presence of clonal hematopoiesis in different age groups, 0.5% of individuals younger than 50 years old, 2% to 3% in elderly individuals, and a remarkable 10% to 20% of elderly individuals above 70 years old showed clonal hematopoiesis. Thus, clonal hematopoiesis does not only occur during normal hematopoiesis but also is strongly correlated with age.
Insight in clonal hematopoiesis and its relationship with leukemia emerged when driver mutations were assessed in individuals with normal clonal hematopoiesis. TET2 mutations were detected in 5% of older individuals with clonal hematopoiesis, but such mutations were not detected in individuals with non-clonal hematopoiesis. This was the first time that a mutation associated with myeloid leukemia was found to be present and compatible with normal hematopoiesis, corroborating the idea that leukemia arises from the acquisition of sequential mutations and that clonal hematopoiesis acts as a pre-leukemic state.
With advancements in DNA exome sequencing, studies have revealed the mutation profile of large cohorts of individuals within different age categories and inclusion criteria (presence of hematological neoplasia, psychiatric and cardiovascular disorders). Individuals with clonal hematopoiesis showed a restricted pattern of mutations in genes involved in different cellular processes. However, the most striking mutation profile, found in more than two-thirds of these individuals, affected the coding sequence of a small number of epi genetic genes, particularly DNMT3A, TET2, and ASXL1.
It may be relevant to distinguish between various types of clonal hematopoiesis. First, individuals with clonal hematopoiesis do not necessarily carry mutations in driver genes. Currently, it is a challenge to detect such clones due to low variant allele frequency (VAF). However, in individuals who do carry cancer-associated mutations, this process is referred to as clonal hematopoiesis of indeterminate potential (CHIP). Thus, in order to meet the definition of CHIP, one must carry driver mutations (DNMT3A and/or TP53, for example) at a VAF of 2% or higher. CHIP by itself does not designate a malignant transformation or other clinical manifestations, but it does share common mutations that are recurrent in hematological disorders such as AML, MDS, myeloproliferative neoplasms (MPNs), and lymphomas. Furthermore, for unknown reasons, only a fraction of individuals with CHIP will actually undergo malignant transformation. However, individuals carrying CHIP have a significantly increased risk of mortality that is largely accounted for an overall increased risk for cardiovascular diseases. Large cohort studies showed that individuals with CHIP have double the risk of developing coronary heart diseases and a four times higher risk to develop early-onset myocardial infarction (MI). CHIP also increases the risk of venous thrombosis 12-fold and is correlated with worse survival outcomes of post-MI-related congestive heart failure. Overall, CHIP is a strong indicator of poor prognosis for several distinct disorders including the development of hematological malignancies and cardiovascular disorders.
Although CHIP is significantly more prevalent in elderly individuals, a causal relation between clonal hematopoiesis and aging and possibly other factors remains to be determined. Indeed, many healthy elderly individuals display clonal hematopoiesis. Specifically, if the mutations that define clones are not leukemia-driver mutations— i.e., occur at a non-fully annotated genetic loci or in genes that have not yet been implicated in malignant transformation—this process is referred to as age-related clonal hematopoiesis (ARCH). Similarly as individuals with CHIP, individuals who display ARCH also have a higher risk of mortality. As a full catalog of leukemia-drives genes is lacking, CHIP and ARCH could represent similar processes (Fig. 1).
Fig1. CLONAL HEMATOPOIESIS. The incidence of clonal hematopoiesis increases with age (left). Somatic mutations occur during normal aging and are typically inconsequential. Some clones may acquire a proliferative advantage, and eventually, blood production will be oligoclonal (right, top). If dominant clones result from leukemia driving mutations (e.g., DNMT3A, TP53), individuals are diagnosed with clonal hematopoiesis of indeterminate potential (CHIP). Age-related clonal hematopoiesis (ARCH) refers to the acquisition of non-driver mutations at an older age. Both processes significantly increase the odds of hematological malignancies and mortality (right, bottom) compared to individuals who do not carry clonal hematopoiesis (CH). HSC, Hematopoietic stem cell.
Although the molecular mechanism of how clonal hematopoiesis arises is far from understood, it is clear that perturbations that occur at the multipotent progenitor and/or HSCs level affect how such clones will behave. As an example in the context of clonal hematopoiesis, loss-of-function mutations in DNMT3A are among the most prevalent in individuals displaying CHIP. This event likely provides mutated clones with an aberrant DNA methylation profile that results in a selective advantage over time, leading to clonal outgrowth.
Even in individuals who do not display detectable levels of clonal hematopoiesis, physiological aging is likely to render clone selection during a lifespan, where HSCs that become more adapted to age-associated changes eventually will replenish mature blood cells. Interestingly, studies in human and other animal models have demonstrated multiple age-associated changes (mechanisms) that play an important role in HSC aging, and those are discussed in the following sections.
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