Clonal hematopoiesis in human aging and disease

In the paper

“As each HSC acquires ~1 exonic mutation per decade of life 3,”

What the sources say

• Not checked yetcites [3] Welch JS The origin and evolution of mutations in acute myeloid leukemia. Cell 150, 264– 278, doi: 10.1016/j.cell.2012.06.023 (2012). 22817890 PMC3407563 source

In the paper

“But in the 1990s, studies of non-random X-chromosome inactivation (XCI) in women led to the discovery that clonal hematopoiesis also occurs in individuals without cancer 18.”

What the sources say

• Not checked yetcites [18] Fey MF Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe. Blood 83, 931– 938 (1994). 8111064 source

In the paper

“The surprising result of this experiment of nature was that clonal hematopoiesis largely results from mutations in a very restricted set of genes.”

In the paper

“This outgrowth, called “clonal hematopoiesis,” is highly prevalent in the elderly population.”

• Also stated in: § Introduction · boosted

  “Indeed, numerous studies have now shown that such outgrowths of mutated blood cells, termed “clonal hematopoiesis,” are highly prevalent in the elderly.”

In the paper

“Importantly, non-random XCI in blood cells was observed to increase in frequency with age, although the underlying mechanism was unclear 19.”

What the sources say

• Not checked yetcites [19] Champion KM, Gilbert JG, Asimakopoulos FA, Hinshelwood S & Green AR Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes. British journal of haematology 97, 920– 926 (1997). 9217198 source

In the paper

“The third most commonly mutated gene was ASXL1, a chromatin regulator, while mutations in splicing factors (SF3B1, SRSF2, PRPF8, U2AF1) were also frequent.”

In the paper

“This was the first demonstration that mutation-driven clonal hematopoiesis occurs in healthy persons 20.”

What the sources say

• Not checked yetcites [20] Busque L Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nature genetics 44, 1179– 1181, doi: 10.1038/ng.2413 (2012). 23001125 PMC3483435 source

In the paper

“Like most cancers, AML generally results from several driver mutations that occur sequentially in the same clone over time 3.”

What the sources say

• Not checked yetcites [3] Welch JS The origin and evolution of mutations in acute myeloid leukemia. Cell 150, 264– 278, doi: 10.1016/j.cell.2012.06.023 (2012). 22817890 PMC3407563 source

In the paper

“Mutations in classical oncogenes and tumor suppressors, such as those involved in cellular growth signaling (JAK2, GNAS, GNB1, CBL) and the DNA damage response (TP53, PPM1D), were seen but were not the most common.”

In the paper

“The size of these mutant clones was massive; in one study, a median of ~18% of blood cells carried the mutations 28.”

What the sources say

• Not checked yetcites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source

In the paper

“A second observation that emerged from these studies was that clonal hematopoiesis is an age-related phenomenon.”

In the paper

“In contrast, 10–20% of individuals age 70 or older harbored a detectable clone.”

In the paper

“If the first mutation to be acquired leads to clonal expansion without malignant transformation, it should be possible to identify a pre-malignant stage in which only the initiating lesion is present 21.”

What the sources say

• Not checked yetcites [21] Reya T, Morrison SJ, Clarke MF & Weissman IL Stem cells, cancer, and cancer stem cells. Nature 414, 105– 111, doi: 10.1038/35102167 (2001). 11689955 source

In the paper

“Instead, nearly two-thirds of clonal hematopoiesis could be accounted for by loss-of-function mutations in just two enzymes involved in DNA methylation, DNMT3A and TET2.”

In the paper

“If just one of these mutations is capable of imparting a fitness advantage to the cell in which it arose, expansions of mutated HSCs, termed “clones”, should be common in aging humans.”

In the paper

“In 2012, mutations in TET2 (a gene coding for an enzyme that oxidizes methylated DNA) were found in ~5% of elderly women with non-random XCI.”

What the sources say

• Not checked yetcites [20] Busque L Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nature genetics 44, 1179– 1181, doi: 10.1038/ng.2413 (2012). 23001125 PMC3483435 source

In the paper

“The third most commonly mutated gene was ASXL1, a chromatin regulator, while mutations in splicing factors (SF3B1, SRSF2, PRPF8, U2AF1) were also frequent.”

In the paper

“It is estimated that humans have 50,000 to 200,000 hematopoietic stem cells (HSCs) 13.”

What the sources say

• Not checked yetcites [13] Lee-Six H Population dynamics of normal human blood inferred from somatic mutations. Nature, doi: 10.1038/s41586-018-0497-0 (2018). PMC6163040 30185910 source

In the paper

“Clonal hematopoiesis is also commonly found in aplastic anemia, a disorder caused by an autoimmune attack on bone marrow progenitor cells that results in severely depressed blood counts 59.”

What the sources say

• Not checked yetcites [59] Yoshizato T Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. N Engl J Med 373, 35– 47, doi: 10.1056/NEJMoa1414799 (2015). 26132940 PMC7478337 source

In the paper

“HSCs from mice with mutations in both Tp53 42 and Ppm1d, a gene encoding a regulator of p53 and other members of the DNA damage response pathway, 43,44 are able to enter cell cycle despite the presence of DNA damage, leading to a stem cell advantage in the setting of cytotoxic drugs.”

What the sources say

• Not checked yetcites [42] Bondar T & Medzhitov R p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell 6, 309– 322, doi: 10.1016/j.stem.2010.03.002 (2010). 20362536 PMC2872065 source
• Not checked yetcites [43] Kahn JD PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 132, 1095– 1105, doi: 10.1182/blood-2018-05-850339 (2018). 29954749 PMC6137556 source
• Not checked yetcites [44] Hsu JI PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy. Cell Stem Cell 23, 700– 713 e706, doi: 10.1016/j.stem.2018.10.004 (2018). 30388424 PMC6224657 source

In the paper

“But many of the most commonly seen mutations in CHIP are also recurrent drivers of AML 64, myelodysplastic syndrome (MDS) 65–67, myeloproliferative neoplasms 68, and certain lymphomas 69,70.”

What the sources say

• Not checked yetcites [64] Cancer Genome Atlas Research N Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368, 2059– 2074, doi: 10.1056/NEJMoa1301689 (2013). 23634996 PMC3767041 source
• Not checked yetcites [65] Bejar R Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 364, 2496– 2506, doi: 10.1056/NEJMoa1013343 (2011). 21714648 PMC3159042 source
• Not checked yetcites [66] Papaemmanuil E Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122, 3616– 3627; quiz 3699, doi: 10.1182/blood-2013-08-518886 (2013). 24030381 PMC3837510 source
• Not checked yetcites [67] Lindsley RC Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N Engl J Med 376, 536– 547, doi: 10.1056/NEJMoa1611604 (2017). 28177873 PMC5438571 source
• Not checked yetcites [68] Nangalia J Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369, 2391– 2405, doi: 10.1056/NEJMoa1312542 (2013). 24325359 PMC3966280 source

In the paper

“Activating mutations in JAK2 allow constitutive signaling though growth factor receptors, thus leading to clonal expansion by enhanced proliferation of cells that carry this mutation 45.”

What the sources say

• Not checked yetcites [45] Kralovics R A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352, 1779– 1790, doi: 10.1056/NEJMoa051113 (2005). 15858187 source

In the paper

“If sequenced deeply enough, a cancer-associated mutation may be detectable in most people over the age of 50 33,”

What the sources say

• Not checked yetcites [33] Young AL, Challen GA, Birmann BM & Druley TE Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun 7, 12484, doi: 10.1038/ncomms12484 (2016). 27546487 PMC4996934 source

In the paper

“Recent studies have implicated genetic predispositions 37,61 as well as the microbiome 62 in the etiology and progression of clonal hematopoiesis.”

What the sources say

• Not checked yetcites [37] Zink F Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742– 752, doi: 10.1182/blood-2017-02-769869 (2017). 28483762 PMC5553576 source
• Not checked yetcites [61] Hinds DA Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood 128, 1121– 1128, doi: 10.1182/blood-2015-06-652941 (2016). 27365426 PMC5085254 source
• Not checked yetcites [62] Meisel M Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557, 580– 584, doi: 10.1038/s41586-018-0125-z (2018). 29769727 PMC6238954 source

In the paper

“Subsequent studies in healthy persons using more sensitive approaches have found the prevalence of clonal hematopoiesis to be much higher, although the biological significance of the smaller clones is unknown 31–33.”

What the sources say

• Not checked yetcites [31] McKerrell T Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep 10, 1239– 1245, doi: 10.1016/j.celrep.2015.02.005 (2015). 25732814 PMC4542313 source
• Not checked yetcites [32] Acuna-Hidalgo R Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life. Am J Hum Genet 101, 50– 64, doi: 10.1016/j.ajhg.2017.05.013 (2017). 28669404 PMC5501773 source
• Not checked yetcites [33] Young AL, Challen GA, Birmann BM & Druley TE Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun 7, 12484, doi: 10.1038/ncomms12484 (2016). 27546487 PMC4996934 source

In the paper

“Mutations in genes encoding core members of the spliceosome are also common in CHIP.”

In the paper

“Instead, changes associated with chronic lymphocytic leukemia (CLL) and losses of sex chromosomes are the most common variants that accumulate in aging36.”

What the sources say

• Not checked yetcites [36] Loh PR Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Nature 559, 350– 355, doi: 10.1038/s41586-018-0321-x (2018). 29995854 PMC6054542 source

In the paper

“The risk of developing clonal hematopoiesis is largely related to the stochastic acquisition of somatic mutations in HSCs during aging.”

In the paper

“HSCs from mice mutant for these genes, Sf3b1 56, Srsf2 57, and U2af1 58, have a competitive disadvantage in vivo, unlike the clonal expansion observed in humans with these mutations.”

What the sources say

• Not checked yetcites [56] Obeng EA Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation. Cancer cell 30, 404– 417, doi: 10.1016/j.ccell.2016.08.006 (2016). 27622333 PMC5023069 source
• Not checked yetcites [57] Kim E SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition. Cancer cell 27, 617– 630, doi: 10.1016/j.ccell.2015.04.006 (2015). 25965569 PMC4429920 source
• Not checked yetcites [58] Shirai CL Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo. Cancer cell 27, 631– 643, doi: 10.1016/j.ccell.2015.04.008 (2015). 25965570 PMC4430854 source

In the paper

“Further complicating the picture, clonal hematopoiesis has been observed in the absence of any known driver mutation 27,37.”

What the sources say

• Not checked yetcites [27] Genovese G Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371, 2477– 2487, doi: 10.1056/NEJMoa1409405 (2014). 25426838 PMC4290021 source
• Not checked yetcites [37] Zink F Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742– 752, doi: 10.1182/blood-2017-02-769869 (2017). 28483762 PMC5553576 source

In the paper

“One important consideration is that the prevalence of clonal hematopoiesis is highly dependent on the sensitivity of the method used to detect it (Fig. 2).”

In the paper

“In contrast to the mutations associated with CHIP, the mutations most commonly seen in aplastic anemia affect the genes PIGA, BCOR, and BCORL1.”

In the paper

“Indeed, in population-based cohorts that underwent exome sequencing, the presence of CHIP was associated with ~10-fold increased relative risk of these malignancies over several years of follow-up 27,28.”

What the sources say

• Not checked yetcites [27] Genovese G Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371, 2477– 2487, doi: 10.1056/NEJMoa1409405 (2014). 25426838 PMC4290021 source
• Not checked yetcites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source

In the paper

“but only clones that reach a certain size are likely to be clinically meaningful.”

In the paper

“For example, copy number gains or losses of DNMT3A, TET2, and ASXL1, are rarely found in surveys of somatic large structural variation 35.”

What the sources say

• Not checked yetcites [35] Jacobs KB Detectable clonal mosaicism and its relationship to aging and cancer. Nature genetics 44, 651– 658, doi: 10.1038/ng.2270 (2012). 22561519 PMC3372921 source

In the paper

“Similar to previous studies, the risk of AML positively correlated with the size of the mutant clone.”

In the paper

“In support of this hypothesis, loss of Tet2 in myeloid cells was sufficient to confer enhanced atherosclerosis.”

In the paper

“In an initial study, this risk could not be explained by cancer deaths but was instead related to increased cardiovascular mortality 28.”

What the sources say

• Not checked yetcites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source

In the paper

“In studies of middle-aged and older individuals, the risk for coronary heart disease was nearly twice as high for individuals with CHIP compared to individuals without CHIP.”

In the paper

“To date, few studies have demonstrated an unequivocal link between CHIP and other diseases of aging.”

In the paper

“Thus, CHIP is likely to be an indicator of poor prognosis for several distinct cardiovascular disorders.”

In the paper

“Furthermore, the mutational spectrum in patients with non-hematologic cancers was altered: HSC mutations in DNA damage response genes such as TP53 and PPM1D were far more prevalent in this setting, likely due to strong selective pressure from exposure to cytotoxic therapies.”

In the paper

“Further analysis revealed that the risk of future ischemic stroke and coronary heart disease was more than doubled in carriers of CHIP (Fig. 3A).”

In the paper

“There is also evidence that Jak2 mutations enhance atherosclerosis in mouse models by altering macrophage function 89.”

What the sources say

• Not checked yetcites [89] Wang W Macrophage Inflammation, Erythrophagocytosis, and Accelerated Atherosclerosis in Jak2 (V617F) Mice. Circ Res 123, e35– e47, doi: 10.1161/CIRCRESAHA.118.313283 (2018). 30571460 PMC6309796 source

In the paper

“An intriguing finding from these studies was that mutations in TP53, JAK2, SF3B1, SRSF2 and U2AF1 were linked to a particularly high risk of developing AML;”

In the paper

“One study of a patient population treated for solid cancers found that CHIP mutations were more prevalent in this group than in populations not selected for cancer 77.”

What the sources say

• Not checked yetcites [77] Coombs CC Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. Cell Stem Cell 21, 374– 382 e374, doi: 10.1016/j.stem.2017.07.010 (2017). 28803919 PMC5591073 source

In the paper

“Several studies have found that CHIP is associated with a 30–40% increased mortality risk 27,28,37.”

What the sources say

• Not checked yetcites [27] Genovese G Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371, 2477– 2487, doi: 10.1056/NEJMoa1409405 (2014). 25426838 PMC4290021 source
• Not checked yetcites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source
• Not checked yetcites [37] Zink F Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742– 752, doi: 10.1182/blood-2017-02-769869 (2017). 28483762 PMC5553576 source

In the paper

“Like several other well-described markers in blood cells, such as red cell distribution width 83, DNA methylation clocks 84, and loss of Y-chromosome 85, CHIP is associated with multiple adverse outcomes in epidemiological studies.”

What the sources say

• Not checked yetcites [83] Patel KV, Ferrucci L, Ershler WB, Longo DL & Guralnik JM Red blood cell distribution width and the risk of death in middle-aged and older adults. Archives of internal medicine 169, 515– 523, doi: 10.1001/archinternmed.2009.11 (2009). 19273783 PMC2765040 source
• Not checked yetcites [84] Horvath S & Raj K DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 19, 371– 384, doi: 10.1038/s41576-018-0004-3 (2018). 29643443 source
• Not checked yetcites [85] Haitjema S Loss of Y Chromosome in Blood Is Associated With Major Cardiovascular Events During Follow-Up in Men After Carotid Endarterectomy. Circ Cardiovasc Genet 10, e001544, doi: 10.1161/CIRCGENETICS.116.001544 (2017). 28768751 source

In the paper

“The risk for early-onset myocardial infarction (MI), defined as heart attack before age 40 in men or age 50 in women, was four times higher in those with CHIP compared to those without CHIP.”

In the paper

“Notably, the risk of malignancy in the carriers of CHIP was associated with the size of the mutant clone, as those who went on to develop malignancy had substantially larger clone sizes than those who did not.”

In the paper

“In addition, blockade of the pro-inflammatory cytokine IL-1B reversed the accelerated atherosclerosis seen in Tet2 mutant mice 86.”

What the sources say

• Not checked yetcites [86] Fuster JJ Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice. Science, doi: 10.1126/science.aag1381 (2017). PMC5542057 28104796 source

In the paper

“Indeed, some individuals with clonal hematopoiesis have virtually all of their blood cells arising from a single mutated HSC 28.”

What the sources say

• Not checked yetcites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source

In the paper

“In 2017, two research groups used mouse models to establish a causal role for CHIP in atherosclerosis.”

In the paper

“Just as CHIP is associated with an increased risk of cardiovascular disease, lower-risk subtypes of MDS are also associated with a doubling of the risk of dying from cardiovascular causes 80.”

What the sources say

• Not checked yetcites [80] Brunner AM Risk and timing of cardiovascular death among patients with myelodysplastic syndromes. Blood Adv 1, 2032– 2040, doi: 10.1182/bloodadvances.2017010165 (2017). 29296849 PMC5728287 source

In the paper

“In this study of primarily middle-aged individuals, the risk of coronary heart disease and ischemic stroke associated with CHIP was as great or greater than that conferred by well-known risk factors for cardiovascular disease, such as circulating LDL-cholesterol levels, smoking, and blood pressure (Fig. 3B).”

In the paper

“However, causality could not be established”

In the paper

“Recent evidence suggests that individuals with post-MI related congestive heart failure who carry CHIP-associated DNMT3A or TET2 mutations have worse survival outcomes than individuals without CHIP 81.”

What the sources say

• Not checked yetcites [81] Dorsheimer L Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure. JAMA Cardiol 4, 25– 33, doi: 10.1001/jamacardio.2018.3965 (2019). 30566180 PMC6439691 source

In the paper

“CHIP has been found to be associated with a 30% increase in the likelihood of having type 2 diabetes (T2D) 28.”

What the sources say

• Not checked yetcites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source

In the paper

“Several studies have found that patients with CHIP and solid tumors or lymphoma have an increased risk of these therapy-related myeloid neoplasms after treatment for the primary disease 73–75.”

What the sources say

• Not checked yetcites [73] Gibson CJ Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma. J Clin Oncol 35, 1598– 1605, doi: 10.1200/JCO.2016.71.6712 (2017). 28068180 PMC5455707 source
• Not checked yetcites [74] Gillis NK Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol 18, 112– 121, doi: 10.1016/S1470-2045(16)30627-1 (2017). 27927582 PMC7771361 source
• Not checked yetcites [75] Takahashi K Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol 18, 100– 111, doi: 10.1016/S1470-2045(16)30626-X (2017). 27923552 PMC5405697 source

In the paper

“Rather, the mutant bone marrow-derived macrophages upregulated many pro-inflammatory molecules, suggesting a potential mechanism for the increase in atherosclerosis.”

In the paper

“Together, these studies provide strong evidence that somatic mutation-driven clonal hematopoiesis has a causal role in cardiovascular disease.”

In the paper

“These immune effector cells are derived from HSCs, so any mutations that occur in HSCs can also potentially alter the immune response or baseline inflammatory state.”

In the paper

“Both groups found that individuals with antecedent clonal hematopoiesis were at ~3 to 5-fold increased risk for developing AML in the subsequent years (Fig. 3A).”

What the sources say

• Not checked yetcites [71] Abelson S Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559, 400– 404, doi: 10.1038/s41586-018-0317-6 (2018). 29988082 PMC6485381 source
• Not checked yetcites [72] Desai P Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med 24, 1015– 1023, doi: 10.1038/s41591-018-0081-z (2018). 29988143 PMC6849383 source

In the paper

“this effect on Il6 expression was independent of the catalytic function of Tet2”

What the sources say

• Not checked yetcites [91] Zhang Q Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389– 393, doi: 10.1038/nature15252 (2015). 26287468 PMC4697747 source

In the paper

“CHIP may underlie some part of the phenomenon termed “inflammaging”, the age-associated increase in systemic inflammation 97”

What the sources say

• Not checked yetcites [97] Franceschi C & Campisi J Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69 Suppl 1, S4– 9, doi: 10.1093/gerona/glu057 (2014). 24833586 source

In the paper

“Several studies have found additional roles for TET2 and DNMT3A in normal T- and B-cell function (Figure 4).”

In the paper

“also found that Il1b, IL8 family chemokines, and other inflammatory mediators show increased expression in Tet2-deficient macrophages challenged with low-density lipoprotein or endotoxin 79,86,92”

What the sources say

• Not checked yetcites [79] Jaiswal S Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med 377, 111– 121, doi: 10.1056/NEJMoa1701719 (2017). 28636844 PMC6717509 source
• Not checked yetcites [86] Fuster JJ Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice. Science, doi: 10.1126/science.aag1381 (2017). PMC5542057 28104796 source
• Not checked yetcites [92] Cull AH, Snetsinger B, Buckstein R, Wells RA & Rauh MJ Tet2 restrains inflammatory gene expression in macrophages. Exp Hematol 55, 56– 70 e13, doi: 10.1016/j.exphem.2017.08.001 (2017). 28826859 source

In the paper

“Another study used CRISPR to mutate Dnmt3a in mouse RAW 264.7 macrophages, and observed increased expression of Cxcl1, Cxcl2, and Il6 in response to endotoxin 87.”

What the sources say

• Not checked yetcites [87] Sano S CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease. Circ Res 123, 335– 341, doi: 10.1161/CIRCRESAHA.118.313225 (2018). 29728415 PMC6054544 source

In the paper

“clone size associates with the risk of leukemia and other adverse outcomes”

In the paper

“was instead reported to be related to a direct interaction between Tet2 and histone deacetylases, resulting in transcriptional repression.”

What the sources say

• Not checked yetcites [91] Zhang Q Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389– 393, doi: 10.1038/nature15252 (2015). 26287468 PMC4697747 source

In the paper

“growing evidence supports a role for the commonly mutated CHIP genes in immune function”

In the paper

“Subsequent studies have confirmed the over-expression of Il6”

What the sources say

• Not checked yetcites [79] Jaiswal S Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med 377, 111– 121, doi: 10.1056/NEJMoa1701719 (2017). 28636844 PMC6717509 source
• Not checked yetcites [86] Fuster JJ Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice. Science, doi: 10.1126/science.aag1381 (2017). PMC5542057 28104796 source
• Not checked yetcites [92] Cull AH, Snetsinger B, Buckstein R, Wells RA & Rauh MJ Tet2 restrains inflammatory gene expression in macrophages. Exp Hematol 55, 56– 70 e13, doi: 10.1016/j.exphem.2017.08.001 (2017). 28826859 source

In the paper

“Humans with mutations in TET2 are also reported to have increased levels of circulating IL8 protein 79.”

What the sources say

• Not checked yetcites [79] Jaiswal S Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med 377, 111– 121, doi: 10.1056/NEJMoa1701719 (2017). 28636844 PMC6717509 source

In the paper

“These molecules are thought to enhance inflammation locally within atherosclerotic plaques by increasing chemotaxis of leukocytes to arterial intima”

What the sources say

• Not checked yetcites [93] Natarajan P, Jaiswal S & Kathiresan S Clonal Hematopoiesis: Somatic Mutations in Blood Cells and Atherosclerosis. Circ Genom Precis Med 11, e001926, doi: 10.1161/CIRCGEN.118.001926 (2018). 29987111 PMC6082163 source

In the paper

“mice deficient in Tet2 developed more severe inflammation in several tissues upon challenge with bacterial endotoxin”

What the sources say

• Not checked yetcites [91] Zhang Q Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389– 393, doi: 10.1038/nature15252 (2015). 26287468 PMC4697747 source

In the paper

“one study found that mast cells from mice that lacked Dnmt3a produced higher levels of IL-6, TNF-alpha, and IL-13 in response to stimulation with IgE in vitro”

What the sources say

• Not checked yetcites [94] Leoni C Dnmt3a restrains mast cell inflammatory responses. Proc Natl Acad Sci U S A 114, E1490– E1499, doi: 10.1073/pnas.1616420114 (2017). 28167789 PMC5338402 source

In the paper

“There is also a report of an exceptional response in a patient with CLL treated by infusion of chimeric antigen receptor (CAR) T-cells in which the CAR construct disrupted one copy of TET2, while the other copy had been previously mutated somatically 96.”

What the sources say

• Not checked yetcites [96] Fraietta JA Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307– 312, doi: 10.1038/s41586-018-0178-z (2018). 29849141 PMC6320248 source

In the paper

“the level of risk for any given individual is likely to be variable”

In the paper

“which potentially explains the accelerated atherosclerosis seen with loss of Tet2 93”

What the sources say

• Not checked yetcites [93] Natarajan P, Jaiswal S & Kathiresan S Clonal Hematopoiesis: Somatic Mutations in Blood Cells and Atherosclerosis. Circ Genom Precis Med 11, e001926, doi: 10.1161/CIRCGEN.118.001926 (2018). 29987111 PMC6082163 source

In the paper

“most studies to date have found evidence of enhanced inflammation when its function is perturbed”

In the paper

“Studies of serial samples have shown that the trajectory of a clone can vary between people.”

What the sources say

• Not checked yetcites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source
• Not checked yetcites [33] Young AL, Challen GA, Birmann BM & Druley TE Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun 7, 12484, doi: 10.1038/ncomms12484 (2016). 27546487 PMC4996934 source

In the paper

“The effect of specific gene variants on various outcomes may be quite different, as has been found in AML 71.”

What the sources say

• Not checked yetcites [71] Abelson S Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559, 400– 404, doi: 10.1038/s41586-018-0317-6 (2018). 29988082 PMC6485381 source

In the paper

“CHIP may be relevant in the adaptive immune response as well.”

In the paper

“this was partially explained by increased expression of the pro-inflammatory cytokine Il6 in dendritic cells and macrophages 91”

What the sources say

• Not checked yetcites [91] Zhang Q Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389– 393, doi: 10.1038/nature15252 (2015). 26287468 PMC4697747 source

In the paper

“enhanced mast cell activity was also seen in a mouse model of allergy 94”

What the sources say

• Not checked yetcites [94] Leoni C Dnmt3a restrains mast cell inflammatory responses. Proc Natl Acad Sci U S A 114, E1490– E1499, doi: 10.1073/pnas.1616420114 (2017). 28167789 PMC5338402 source

In the paper

“Other studies have found links between CHIP and chronic obstructive pulmonary disease (COPD) 37,63.”

What the sources say

• Not checked yetcites [37] Zink F Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742– 752, doi: 10.1182/blood-2017-02-769869 (2017). 28483762 PMC5553576 source
• Not checked yetcites [63] Buscarlet M DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130, 753– 762, doi: 10.1182/blood-2017-04-777029 (2017). 28655780 source