Clonal Hematopoiesis Of Indeterminate Potential
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Clonal hematopoiesis of indeterminate potential, or CHIP, is a common aging-related phenomenon in which hematopoietic stem cells (HSCs) or other early blood cell progenitors contribute to the formation of a genetically distinct subpopulation of
blood cell A blood cell (also called a hematopoietic cell, hemocyte, or hematocyte) is a cell produced through hematopoiesis and found mainly in the blood. Major types of blood cells include red blood cells (erythrocytes), white blood cells (leukocytes), ...
s. As the name suggests, this subpopulation in the blood is characterized by a shared unique
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
in the cells'
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
; it is thought that this subpopulation is "clonally" derived from a single founding cell and is therefore made of genetic "clones" of the founder. The establishment of a clonal population may occur when a stem or progenitor cell acquires one or more somatic mutations that give it a competitive advantage in
hematopoiesis Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...
over the stem/progenitor cells without these mutations. Alternatively, clonal hematopoiesis may arise without a driving mutation, through mechanisms such as neutral drift in the stem cell population. Clonal hematopoiesis may occur in people who are completely healthy but has also been found in people with hematologic diseases. The clonal population may vary in size depending on the person, where it can be less than 2% of the blood or, at the other end, can sometimes grow close to 100%. The incidence of clonal hematopoiesis has been found to rise dramatically with age. Recent studies have demonstrated that less than 1% of the population under age 40 but approximately 10-20% of the population over age 70 has observable clonal hematopoiesis. Having clonal hematopoiesis has been linked to a more than 10-fold increased risk of developing a blood cancer, though the overall likelihood is still low. Clonal hematopoiesis does not typically give rise to noticeable symptoms, but does lead to increased risk of
cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
. Patients with solid tumors or lymphoma and clonal hematopoiesis have been shown to have an inferior outcome.


History

The first major evidence for the existence of prevalent clonal hematopoiesis in healthy people was put forth in the 1990s. Using the
HUMARA assay HUMARA assay is one of the most widely used methods to determine the clonal origin of a tumor. The method is based on X chromosome inactivation and it takes advantage of the different methylation status of the gene HUMARA (short for human androgen r ...
, scientists found that there was nonrandom
X-inactivation X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into ...
of the
X chromosome The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...
in the blood of some healthy women. This means that a greater than expected proportion of the blood had the silencing of one specific X chromosome in the chromosome pair. Just as the observation of the same DNA mutation in a subset of cells suggests a single founding source, this X-inactivation skew suggests that a greater than expected number of cells are being generated from the same precursor. Importantly, these findings described an increase in this nonrandom skewing with increasing age, hinting that unobserved mutations acquired with age could be driving a clonal expansion. In a similar vein, other studies using the HUMARA technology had found that hematologic malignancies are clonal diseases even when there is no apparent chromosomal abnormality, and that there are pre-leukemic clonal populations which precede acute myeloid leukemia (AML). As the HUMARA assay is based on the
epigenetic In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...
state of cells, the underlying genetic determinants of the clonal expansion remained to be uncovered. This set of evidence led to the suggestion in 2005 that driving mutations in leukemia are acquired in a step-wise manner. This model has received support from studies showing subpopulations of blood cells harboring initiating but not late somatic mutations in patients with chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), and AML. The combination of these two ideas, that clonal hematopoiesis might be common in the elderly population and that AML evolves from pre-leukemic populations, led to the hypothesis that malignancy-associated mutations could also contribute to asymptomatic clonal hematopoiesis in healthy individuals. 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''. 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. In combination, these studies have demonstrated the widespread incidence of clonal hematopoiesis in the healthy adult population and have stimulated further efforts to broaden our understanding of clonal hematopoiesis in health and disease. 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 2% threshold was chosen in part because of technical limitations (i.e., analytic sensitivity of clinically available sequencing assays) but also because very small clones are of unclear clinical significance.


Population genetics

The advent of next-generation DNA sequencing has allowed for the targeted identification of somatic mutations involved in clonal hematopoiesis at the population level. The studies undertaken as of 2017 are largely consistent in their main findings. 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. Indeed, the evidence from these studies suggests that between 10% and 20% of the population over age 70 have clonal hematopoiesis. In the U.S. alone, this means that, at the low end, some 2,975,000 seniors over 70 years of age are living with this condition. The other main common finding is that there are many different mutations involved in clonal hematopoiesis. Many of these fall into the categories of epigenetic regulators ( ''DNMT3a'', ''TET2'', and ''
ASXL1 Putative Polycomb group protein ASXL1 is a protein that in humans is encoded by the ''ASXL1'' gene. In ''Drosophila'', the Additional sex combs (Asx) gene encodes a chromatin-binding protein required for normal determination of segment identity i ...
''), signaling proteins ( ''JAK2''),
spliceosome A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs ( snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to sp ...
components (''
SF3B1 Splicing factor 3B subunit 1 is a protein that in humans is encoded by the ''SF3B1'' gene. Function This gene encodes subunit 1 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and U2 spliceosom ...
'' and ''SRSF2''), or members of the DNA damage response (''
TP53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
'' and ''
PPM1D Protein phosphatase 1D is an enzyme that in humans is encoded by the ''PPM1D'' gene. The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell ...
''). Many people identified as having clonal hematopoiesis have a mutation in a single gene, though a significant number have mutations in two or more genes. The number and variety of observed mutations suggests that these mutations may contribute to clonal hematopoiesis by several distinct mechanisms, discussed in more detail below. While
DNMT3A DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the ''DNMT3A'' gene. This enzyme is ...
is the most prevalent driver mutation,
TET2 Tet methylcytosine dioxygenase 2 (''TET2'') is a human gene. It resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Function ' ...
and splicing gene mutations are more prevalent in those over 75 years old. 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). A study employing the ultra-sensitive digital droplet PCR method found that 95% of studied individuals (19 out of 20) between the ages of 50 and 70 had at least low-level clonal hematopoiesis. This finding does not necessarily conflict with earlier reports that clonal hematopoiesis is not ubiquitous in this age bracket, as these previous studies' experimental designs compels the use of a higher threshold to identify legitimate clonal hematopoiesis. Ongoing studies are examining what genetic and epidemiological factors may influence the acquisition of mutations in clonal hematopoiesis. Once mutated, the HSCs with a relative fitness advantage give rise to clones capable of expansion, in a type of Darwinian selection.


Biology

Clonal hematopoiesis is thought to originate with the hematopoietic stem cells that make blood. An adult human has approximately 10,000 to 20,000 HSCs. The fact that these cells are maintained for life and each HSC may acquire about one mutation in a protein-coding
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
each decade means that an elderly individual will have a certain amount of genetic mosaicism, or a variety of cells with different unique mutations, within their HSC population. However, this does not lead to clonal hematopoiesis in all cases. 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.


Candidate driver mutations

There are several general mechanisms by which a mutation could provide such an advantage and it is likely that the mutations found in clonal hematopoiesis act through different pathways. First, a mutation could provide a growth advantage, causing HSCs to divide more rapidly and contribute a larger proportion of the mature blood cells. This may be the case for mutations in genes related to signaling, such as that which causes the activating V617F substitution in the JAK2 signaling protein. 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. Other mechanisms are more likely to be associated with the disruption of epigenetic regulators, which comprises 80% of observed mutations in clonal hematopoiesis. A third potential mechanism of action is that the mutation makes the HSC-derived progenitor cells less able to differentiate into mature blood cells. This would allow these cells to continue to divide even after they would have normally stopped, since progenitor cells may divide whereas normal mature blood cells cannot. A fourth possibility is that the mutation makes the progenitor cells and cells derived from them more like stem cells in their ability to keep dividing. 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. A final possibility is that a gradient of epigenetic states is created in the HSC and progenitor cells and the cells with the most favorable epigenetics are able to grow out faster than unmutated cells.


Non-candidate-driver mechanisms

An expansion of blood cells from a single source does not necessarily require a mutation to act as the driving force. A large proportion of the population who exhibit clonal hematopoiesis have no identifiable mutations in known candidate driver genes. 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. Another explanation is that a process of "neutral drift" causes the predominance of a clonal stem cell population over time. In this scenario, all stem cells have an equal proliferative potential but some of them die out in a stochastic manner leading some of the remaining cells to proliferate to replace them. This can be equated to a game of chance where all players start with the same odds of winning. As the game is played, winners and losers will arise despite the equal starting positions.


Implications for human health

Clonal hematopoiesis by itself is not considered to be a hematologic cancer; nevertheless, evidence is mounting that this condition may adversely affect human health. It has been proposed to label the group of individuals who have clonal hematopoiesis defined by a mutation in a malignancy-associated gene but without evidence of disease (such as
cytopenia Cytopenia is a reduction in the number of mature blood cells. It can have many causes, and commonly occurs in people with cancer being treated with radiation therapy or chemotherapy. Types * Anemia – a reduction of the red blood cells in the bo ...
,
dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs (macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopic ...
or immature "blast" cells in the bone marrow) as having Clonal Hematopoiesis of Indeterminate Potential (CHIP). 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. This cutoff may ultimately depend on whether clones must reach a certain size before influencing health. The level at which a clone begins to have a potential clinical impact is an open question, though there is already data to suggest larger clones have a larger effect on health. The presence of clonal hematopoiesis/CHIP has been shown to increase blood cancer risk and is correlated with an increased risk of mortality overall. This is true both of clonal hematopoiesis with known candidate drivers as well as in cases without such drivers.


Blood cancer risk

One area of health that CHIP has been definitively shown to influence is the risk of progression to blood cancer. In a given year, a tiny fraction of the general population will develop a hematologic cancer such as myelodysplastic syndrome (MDS) or AML; it is estimated that just 3 to 4 people per 100,000 will get MDS in a given year, and 4 people per 100,000 will develop AML. With CHIP, the risk of acquiring a hematologic malignancy like MDS or AML is increased more than 10-fold. Despite this increased risk, people with CHIP are still at low overall risk for developing a blood cancer, with only about 0.5-1.0% transformation per year. The risk of transformation to myeloid malignancy depends on the specific mutation and the size of the clone. Single
DNMT3A DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the ''DNMT3A'' gene. This enzyme is ...
mutations have the lowest risk of progression, while splicing factor genes,
JAK2 Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF ...
,
TP53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
,
IDH1 Isocitrate dehydrogenase 1 (NADP+), soluble is an enzyme that in humans is encoded by the ''IDH1'' gene on chromosome 2. Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to ...
,
IDH2 Isocitrate dehydrogenase ADP mitochondrial is an enzyme that in humans is encoded by the ''IDH2'' gene. Isocitrate dehydrogenases are enzymes that catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong ...
,
FLT3 Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3 with fms standing for "feline McDonough sarcoma"), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in human ...
, and
RUNX1 Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) and it is a protein that is encoded by the ''RUNX1'' gene, in humans. RUNX1 is a transcription facto ...
have the highest risk. The clonal hematopoiesis risk score (CHRS) can be used to estimate the risk of progression to myeloid malignancy. CHRS predicts high, intermediate, or low risk based on the presence or absence of mutations in high-risk genes, the clone size, number of different mutations, findings of
macrocytosis Macrocytosis is a condition where red blood cells are larger than normal. These enlarged cells, also known as macrocytes, are defined by a mean corpuscular volume (MCV) that exceeds the upper reference range established by the laboratory and he ...
(MCV ≥100 fL),
anisocytosis Anisocytosis is a medical term meaning that a patient's red blood cells are of unequal size. This is commonly found in anemia and other blood conditions. False diagnostic flagging may be triggered on a complete blood count by an elevated WBC count ...
(RDW ≥ 15%), cytopenias (
anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
,
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
, or
thrombocytopenia In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...
) and age ≥ 65 years.


Cardiovascular risk

A second area of health that may be affected by CHIP is the risk for
heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
and
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
. A strong association between CHIP and heart attack/ischemic stroke has been identified in one human genetic dataset, where CHIP was a stronger predictor of heart attack/stroke than if a patient was a smoker, had hypertension, had high cholesterol, or was overweight. In this study, which shows correlation but not causation, people with CHIP were 2.3 times more likely to have a heart attack, or 4.4 times as likely if the variant allele frequency (VAF, a measure of clone size) in their blood was greater than 0.10, than matched controls without CHIP. 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. In addition to heart attack and stroke, human studies further suggest an association of CHIP with
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...
and cardiac
arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...
s. The idea of CHIP having a causal role in human heart attacks/strokes has been given support by a 2017 study that showed impairment of the ''Tet2'' CHIP gene in mice causally led to accelerated atherosclerosis, and this finding in mice has been independently validated. 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 and a large multi-cohort study published in 2017 appears to confirm the causal link between CHIP and cardiovascular disease in humans.


Comorbidities

In addition to its effects on those who would otherwise be considered healthy, CHIP may have implications in certain disease contexts. It has been shown that patients with CHIP who receive autologous stem cell transplantation (ASCT) as part of their treatment for
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...
have worse outcomes than patients without CHIP. The poorer prognosis for these patients is due to both an increase in subsequent therapy-related myeloid neoplasms and increased risk for cardiovascular mortality. Clonal expansion may be related to inflammaging, the low-level systemic inflammation implicated in age-related chronic illnesses. Aging and persistent inflammation both exhaust normal
hematopoietic stem cells Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the ...
by requiring increased proliferation to replenish immune cells. CHIP has been documented in people with HIV infection and autoimmune disease.
Interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...
s,
Interleukin-6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...
,
TNF-alpha Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
and the
TGF-beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
pathway are all thought to play a role in inflammaging as it relates to hematologic malignancies. Inherited
bone marrow failure Bone marrow failure occurs in individuals who produce an insufficient amount of red blood cells, white blood cells or platelets. Red blood cells transport oxygen to be distributed throughout the body's tissue. White blood cells fight off infections ...
syndromes carry a risk of myeloid malignancy, particularly when there are germ line mutations in
CEBPA CCAAT/enhancer-binding protein alpha is a protein encoded by the ''CEBPA'' gene in humans. CCAAT/enhancer-binding protein alpha is a transcription factor involved in the differentiation of certain blood cells. For details on the CCAAT structural m ...
,
DDX41 Probable ATP-dependent RNA helicase DDX41 is an enzyme that in humans is encoded by the ''DDX41'' gene. DEAD box proteins, characterized by the conserved motif Asp- Glu- Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a numbe ...
,
GATA2 GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of ...
,
RUNX1 Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) and it is a protein that is encoded by the ''RUNX1'' gene, in humans. RUNX1 is a transcription facto ...
, or SAMD9/9L. Examples include ribosomopathies such as Schwachman-Diamond syndrome, in which mutations in
EIF6 Eukaryotic translation initiation factor 6 (EIF6), also known as Integrin beta 4 binding protein (ITGB4BP), is a human gene. Hemidesmosomes are structures which link the basal lamina to the intermediate filament cytoskeleton. An important functi ...
may lead to aberrant
p53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
activation;
Severe Congenital Neutropenia Severe congenital neutropenia (SCN), also often known as Kostmann syndrome or disease, is a group of rare disorders that affect myelopoiesis, causing a congenital form of neutropenia, usually without other physical malformations. SCN manifests in ...
, in which
CSF3R The granulocyte colony-stimulating factor receptor (G-CSF-R) also known as CD114 (Cluster of Differentiation 114) is a protein that in humans is encoded by the ''CSF3R'' gene. G-CSF-R is a cell-surface receptor for the granulocyte colony-stimula ...
mutation may lead to myeloid hyperproliferation; telomeropathies such as
dyskeratosis congenita Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, an ...
with acquired mutations in the
TERT Tert may refer to: * ''tert''-, a chemical descriptor prefix used to designate tertiary atoms in molecules * Telomerase reverse transcriptase Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of t ...
promoter, and
Fanconi anemia Fanconi anemia (FA) is a rare, autosomal recessive genetic disease characterized by aplastic anemia, congenital defects, endocrinological abnormalities, and an increased incidence of developing cancer. The study of Fanconi anemia has improve ...
. Inherited
DNMT3A DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the ''DNMT3A'' gene. This enzyme is ...
mutations cause Tatton-Brown-Rahman syndrome, characterized by larger body habitus and intellectual disability. Inherited
bone marrow failure Bone marrow failure occurs in individuals who produce an insufficient amount of red blood cells, white blood cells or platelets. Red blood cells transport oxygen to be distributed throughout the body's tissue. White blood cells fight off infections ...
syndromes represent a kind of premature aging of the bone marrow. In patients with these syndromes and in elderly patients, mutations associated with Clonal Hematopoiesis may arise as an adaptive response to a progressively deteriorating hematopoietic niche, i.e., a depleting pool of
Hematopoietic stem cells Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the ...
. The mutated stem cells then acquire a self-renewal advantage.


Treatment

There are currently no therapies for slowing or targeting CHIP mutations. Together with the fact that progression from CHIP to outright hematologic malignancy remains infrequent, medical experts have argued against preemptive screening for CHIP but suggest routine follow-up for incidental CHIP findings.


Associated disorders

Clonal hematopoiesis is sometimes compared to the unrelated blood disorders of monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B-cell lymphocytosis (MBL) to which it bears similarities in its apparent priming for more advanced hematologic disease combined with a lack of symptoms and overall low risk of progression. The acquisition of additional mutations can cause CHIP to transform into the related blood disorders MDS and AML. Clonal Cytopenias of Undetermined Significance (CCUS) is defined as: *One or more somatic mutations otherwise found in patients with myeloid neoplasms detected in bone marrow or peripheral blood cells with an allele burden of ≥ 2% *Persistent cytopenia (≥ 4 months) in one or more peripheral blood cell lineages *Diagnostic criteria of myeloid neoplasm not fulfilled *All other causes of cytopenia and molecular aberration excluded CCUS has a much higher risk of progression to MDS/AML than CHIP. The most frequent CCUS mutations are in epigenetic regulators (
DNMT3A DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the ''DNMT3A'' gene. This enzyme is ...
,
TET2 Tet methylcytosine dioxygenase 2 (''TET2'') is a human gene. It resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Function ' ...
, and
ASXL1 Putative Polycomb group protein ASXL1 is a protein that in humans is encoded by the ''ASXL1'' gene. In ''Drosophila'', the Additional sex combs (Asx) gene encodes a chromatin-binding protein required for normal determination of segment identity i ...
), RNA splicing factors (
SF3B1 Splicing factor 3B subunit 1 is a protein that in humans is encoded by the ''SF3B1'' gene. Function This gene encodes subunit 1 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and U2 spliceosom ...
, SRSF2),
TP53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
, and
PPM1D Protein phosphatase 1D is an enzyme that in humans is encoded by the ''PPM1D'' gene. The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell ...
. It is likely that a mutational progression occurs, such that splicing factors are mutated early in the development of MDS, while mutations in signaling pathways (
FLT3 Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3 with fms standing for "feline McDonough sarcoma"), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in human ...
,
PTPN11 Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in hu ...
, and RAS) and transcription factors (
CEBPA CCAAT/enhancer-binding protein alpha is a protein encoded by the ''CEBPA'' gene in humans. CCAAT/enhancer-binding protein alpha is a transcription factor involved in the differentiation of certain blood cells. For details on the CCAAT structural m ...
and
RUNX1 Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) and it is a protein that is encoded by the ''RUNX1'' gene, in humans. RUNX1 is a transcription facto ...
) occur as a late event.


See also

*
Acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
*
Haematopoiesis Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...
*
Hematopoietic stem cell Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the ...
*
Hematopoietic stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce ...
*
Hematology Hematology (American and British English spelling differences#ae and oe, spelled haematology in British English) is the branch of medicine concerned with the study of the cause, prognosis, treatment, and prevention of diseases related to bloo ...
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Myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...
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Myeloproliferative neoplasm Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. ''Myelo'' refers to the bone marrow, ''proliferative'' describes the rapid grow ...


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{{Reflist, 30em Hematology Blood