Clonal hematopoiesis
[1][3] Alternatively, clonal hematopoiesis may arise without a driving mutation, through mechanisms such as neutral drift in the stem cell population.
[4][5] Clonal hematopoiesis does not typically give rise to noticeable symptoms, but does lead to increased risk of cardiovascular disease.
[17] As the HUMARA assay is based on the epigenetic state of cells, the underlying genetic determinants of the clonal expansion remained to be uncovered.
[1] This view gained mechanistic support in 2012 when it was found a number of the women who showed evidence for clonal hematopoiesis through X-inactivation skew also had mutations in the hematologic-malignancy-associated gene TET2.
[25] In 2014, several independent studies confirmed the presence of malignancy-associated mutations in the blood of individuals who have no clinical signs of hematologic malignancy.
The term "clonal hematopoiesis of indeterminate potential" (CHIP) was proposed later that year to describe persons who do not have a malignancy meeting World Health Organization diagnostic criteria, yet have somatic mutations in hematopoietic stem and progenitor cells involving genes that have been associated with hematological malignancy, and these mutations are present in blood cells with a variant allele frequency of at least 2%.
The advent of next-generation DNA sequencing has allowed for the targeted identification of somatic mutations involved in clonal hematopoiesis at the population level.
One common finding has been that observable clonal hematopoiesis is virtually absent from the under-40 population, with a sharp uptick in frequency past 60 years of age.
Many of these fall into the categories of epigenetic regulators (DNMT3a, TET2, and ASXL1), signaling proteins (JAK2), spliceosome components (SF3B1 and SRSF2), or members of the DNA damage response (TP53 and PPM1D).
[27] There is also limited evidence suggesting clonal hematopoiesis may be ubiquitous in healthy adults, albeit at extremely low levels (less than 0.1% of peripheral blood cells).
Once mutated, the HSCs with a relative fitness advantage give rise to clones capable of expansion, in a type of Darwinian selection.
It is only when the genetic mutation confers a selective advantage on its host or there is another favorable stem cell dynamic that there is a clonal expansion.
First, a mutation could provide a growth advantage, causing HSCs to divide more rapidly and contribute a larger proportion of the mature blood cells.
Mutations in the DNA damage response genes would appear more likely to act via a second mechanism: allowing for HSC survival and proliferation under normally lethal cytotoxic stress.
The previous two possibilities are very similar in terms of physiologic outcome and mainly differ on what is happening at the DNA level: whether differentiation genes are suppressed or a stem cell program is upregulated.
[4][8] One possible explanation is that among a naturally-occurring spectrum of inheritable epigenetic states, there are those which augment the self-renewal or proliferation of a stem cell and its progeny.
[32] Clonal hematopoiesis by itself is not considered to be a hematologic cancer; nevertheless, evidence is mounting that this condition may adversely affect human health.
[1][3][33] A clonal involvement (sometimes referred to simply as the size of a "clone") of 2% of the blood has been tentatively proposed as a cutoff, though there is discussion that a lower floor that is more inclusive could also be appropriate.
[5] It has also been found that there is an increased risk of cardiovascular mortality in patients who exhibit CHIP and receive self-derived stem cell transplantation.
[11] The possibility of somatic mutations in the blood contributing not only to cancer risk but also to heart attack and stroke has generated much discussion in top-level scientific publications[42][43] and a large multi-cohort study published in 2017 appears to confirm the causal link between CHIP and cardiovascular disease in humans.
[48] Inherited bone marrow failure syndromes carry a risk of myeloid malignancy, particularly when there are germ line mutations in CEBPA, DDX41, GATA2, RUNX1, or SAMD9/9L.
