352:. 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
118:
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.
236:
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.
2331:
C.; Schmidt, Heather K.; Kalicki-Veizer, Joelle M.; Lu, Charles; Zhang, Qunyuan; Lin, Ling; O'Laughlin, Michelle D.; McMichael, Joshua F.; Delehaunty, Kim D.; Fulton, Lucinda A.; Magrini, Vincent J.; McGrath, Sean D.; Demeter, Ryan T.; Vickery, Tammi L.; Hundal, Jasreet; Cook, Lisa L.; Swift, Gary W.; Reed, Jerry P.; Alldredge, Patricia A.; Wylie, Todd N.; Walker, Jason R.; Watson, Mark A.; Heath, Sharon E.; Shannon, William D.; Varghese, Nobish; Nagarajan, Rakesh; Payton, Jacqueline E.; Baty, Jack D.; Kulkarni, Shashikant; Klco, Jeffery M.; Tomasson, Michael H.; Westervelt, Peter; Walter, Matthew J.; Graubert, Timothy A.; DiPersio, John F.; Ding, Li; Mardis, Elaine R.; Wilson, Richard K. (20 July 2012).
245:
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.
131:
55:
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
266:. 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.
232:
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.
127:
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.
959:
Koistinen, Heikki A.; Ladenvall, Claes; Getz, Gad; Correa, Adolfo; Banahan, Benjamin F.; Gabriel, Stacey; Kathiresan, Sekar; Stringham, Heather M.; McCarthy, Mark I.; Boehnke, Michael; Tuomilehto, Jaakko; Haiman, Christopher; Groop, Leif; Atzmon, Gil; Wilson, James G.; Neuberg, Donna; Altshuler, David; Ebert, Benjamin L. (25 December 2014).
188:). 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
46:; 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
2044:
Shlush, Liran I.; Zandi, Sasan; Mitchell, Amanda; Chen, Weihsu Claire; Brandwein, Joseph M.; Gupta, Vikas; Kennedy, James A.; Schimmer, Aaron D.; Schuh, Andre C.; Yee, Karen W.; McLeod, Jessica L.; Doedens, Monica; Medeiros, Jessie J. F.; Marke, Rene; Kim, Hyeoung Joon; Lee, Kwon; McPherson, John D.;
1299:
Gibson, Christopher J.; Lindsley, R. Coleman; Tchekmedyian, Vatche; Mar, Brenton G.; Shi, Jiantao; Jaiswal, Siddhartha; Bosworth, Alysia; Francisco, Liton; He, Jianbo; Bansal, Anita; Morgan, Elizabeth A.; Lacasce, Ann S.; Freedman, Arnold S.; Fisher, David C.; Jacobsen, Eric; Armand, Philippe; Alyea,
283:
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
2686:
Schuermans, A; Vlasschaert, C; Nauffal, V; Cho, SMJ; Uddin, MM; Nakao, T; Niroula, A; Klarqvist, MDR; Weeks, LD; Lin, AE; Saadatagah, S; Lannery, K; Wong, M; Hornsby, W; Lubitz, SA; Ballantyne, C; Jaiswal, S; Libby, P; Ebert, BL; Bick, AG; Ellinor, PT; Natarajan, P; Honigberg, MC (11 November 2023).
2634:
Yu, B; Roberts, MB; Raffield, LM; Zekavat, SM; Nguyen, NQH; Biggs, ML; Brown, MR; Griffin, G; Desai, P; Correa, A; Morrison, AC; Shah, AM; Niroula, A; Uddin, MM; Honigberg, MC; Ebert, BL; Psaty, BM; Whitsel, EA; Manson, JE; Kooperberg, C; Bick, AG; Ballantyne, CM; Reiner, AP; Natarajan, P; Eaton, CB
1862:
Chung, Stephen S.; Kim, Eunhee; Park, Jae H.; Chung, Young Rock; Lito, Piro; Teruya-Feldstein, Julie; Hu, Wenhuo; Beguelin, Wendy; Monette, Sebastien; Duy, Cihangir; Rampal, Raajit; Telis, Leon; Patel, Minal; Kim, Min Kyung; Huberman, Kety; Bouvier, Nancy; Berger, Michael F.; Melnick, Ari M.; Rosen,
1228:
da Silva-Coelho, Pedro; Kroeze, Leonie I.; Yoshida, Kenichi; Koorenhof-Scheele, Theresia N.; Knops, Ruth; van de Locht, Louis T.; de Graaf, Aniek O.; Massop, Marion; Sandmann, Sarah; Dugas, Martin; Stevens-Kroef, Marian J.; Cermak, Jaroslav; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano,
253:
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
222:
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
79:
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
235:
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
126:
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
54:
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
2718:
Fuster, José J.; MacLauchlan, Susan; Zuriaga, María A.; Polackal, Maya N.; Ostriker, Allison C.; Chakraborty, Raja; Wu, Chia-Ling; Sano, Soichi; Muralidharan, Sujatha; Rius, Cristina; Vuong, Jacqueline; Jacob, Sophia; Muralidhar, Varsha; Robertson, Avril A. B.; Cooper, Matthew A.; Andrés, Vicente;
2330:
Welch, John S.; Ley, Timothy J.; Link, Daniel C.; Miller, Christopher A.; Larson, David E.; Koboldt, Daniel C.; Wartman, Lukas D.; Lamprecht, Tamara L.; Liu, Fulu; Xia, Jun; Kandoth, Cyriac; Fulton, Robert S.; McLellan, Michael D.; Dooling, David J.; Wallis, John W.; Chen, Ken; Harris, Christopher
1812:
Damm, Frederik; Mylonas, Elena; Cosson, Adrien; Yoshida, Kenichi; Della Valle, Véronique; Mouly, Enguerran; Diop, M'boyba; Scourzic, Laurianne; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Kikushige, Yoshikane; Davi, Frederick; Lambert, Jérôme; Gautheret, Daniel; Merle-Béral,
367:
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
231:
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
2921:
Dharan NJ, Yeh P, Bloch M, Yeung MM, Baker D, Guinto J, Roth N, Ftouni S, Ognenovska K, Smith D, Hoy JF, Woolley I, Pell C, Templeton DJ, Fraser N, Rose N, Hutchinson J, Petoumenos K, Dawson SJ, Polizzotto MN, Dawson MA; ARCHIVE Study Group. HIV is associated with an increased risk of age-related
107:
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.
2509:
McKerrell, Thomas; Park, Naomi; Moreno, Thaidy; Grove, Carolyn S.; Ponstingl, Hannes; Stephens, Jonathan; Crawley, Charles; Craig, Jenny; Scott, Mike A.; Hodkinson, Clare; Baxter, Joanna; Rad, Roland; Forsyth, Duncan R.; Quail, Michael A.; Zeggini, Eleftheria; Ouwehand, Willem; Varela, Ignacio;
315:
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,
2110:
Busque, Lambert; Patel, Jay P.; Figueroa, Maria E.; Vasanthakumar, Aparna; Provost, Sylvie; Hamilou, Zineb; Mollica, Luigina; Li, Juan; Viale, Agnes; Heguy, Adriana; Hassimi, Maryam; Socci, Nicholas; Bhatt, Parva K.; Gonen, Mithat; Mason, Christopher E.; Melnick, Ari; Godley, Lucy A.; Brennan,
873:
Genovese, Giulio; Kähler, Anna K.; Handsaker, Robert E.; Lindberg, Johan; Rose, Samuel A.; Bakhoum, Samuel F.; Chambert, Kimberly; Mick, Eran; Neale, Benjamin M.; Fromer, Menachem; Purcell, Shaun M.; Svantesson, Oscar; Landén, Mikael; Höglund, Martin; Lehmann, Sören; Gabriel, Stacey B.; Moran,
492:
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
117:
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
244:
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
958:
Jaiswal, Siddhartha; Fontanillas, Pierre; Flannick, Jason; Manning, Alisa; Grauman, Peter V.; Mar, Brenton G.; Lindsley, R. Coleman; Mermel, Craig H.; Burtt, Noel; Chavez, Alejandro; Higgins, John M.; Moltchanov, Vladislav; Kuo, Frank C.; Kluk, Michael J.; Henderson, Brian; Kinnunen, Leena;
204:
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'
479:
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
95:
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
208:
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.
1106:
McKerrell, T; Park, N; Moreno, T; Grove, CS; Ponstingl, H; Stephens, J; Understanding
Society Scientific, Group.; Crawley, C; Craig, J; Scott, MA; Hodkinson, C; Baxter, J; Rad, R; Forsyth, DR; Quail, MA; Zeggini, E; Ouwehand, W; Varela, I; Vassiliou, GS (3 March 2015).
80:
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
2623:
Goldman EA, Spellman PT, Agarwal A. Defining clonal hematopoiesis of indeterminate potential: evolutionary dynamics and detection under aging and inflammation. Cold Spring Harb Mol Case Stud. 2023 May 9;9(2):a006251. doi: 10.1101/mcs.a006251. PMID: 36889927; PMCID:
217:
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
269:
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.
1762:
Kikushige, Yoshikane; Ishikawa, Fumihiko; Miyamoto, Toshihiro; Shima, Takahiro; Urata, Shingo; Yoshimoto, Goichi; Mori, Yasuo; Iino, Tadafumi; Yamauchi, Takuji; Eto, Tetsuya; Niiro, Hiroaki; Iwasaki, Hiromi; Takenaka, Katsuto; Akashi, Koichi (16 August 2011).
384:
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
84:. 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
2911:
Craver BM, El Alaoui K, Scherber RM, Fleischman AG. The
Critical Role of Inflammation in the Pathogenesis and Progression of Myeloid Malignancies. Cancers (Basel). 2018 Apr 3;10(4):104. doi: 10.3390/cancers10040104. PMID: 29614027; PMCID:
1577:
Fialkow, P. J.; Singer, J. W.; Adamson, J. W.; Berkow, R. L.; Friedman, J. M.; Jacobson, R. J.; Moohr, J. W. (5 July 1979). "Acute nonlymphocytic leukemia: expression in cells restricted to granulocytic and monocytic differentiation".
1525:
Champion, K. M.; Gilbert, J. G.; Asimakopoulos, F. A.; Hinshelwood, S.; Green, A. R. (1 June 1997). "Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes".
1300:
Edwin P.; Koreth, John; Ho, Vincent; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome; Nikiforow, Sarah; Forman, Stephen J.; Michor, Franziska; Neuberg, Donna; Bhatia, Ravi; Bhatia, Smita; Ebert, Benjamin L. (9 January 2017).
2965:
Tovy A, Rosas C, Gaikwad AS, et al. Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome. Haematologica. 2022;107(4):887-898. Published 2022 Apr 1. doi:10.3324/haematol.2021.278990
108:
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
2974:
DeZern AE, Malcovati L, Ebert BL. CHIP, CCUS, and Other
Acronyms: Definition, Implications, and Impact on Practice. Am Soc Clin Oncol Educ Book. 2019 Jan;39:400-410. doi: 10.1200/EDBK_239083. Epub 2019 May 17. PMID:
278:
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
199:
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
1813:
Hélène; Sutton, Laurent; Dessen, Philippe; Solary, Eric; Akashi, Koichi; Vainchenker, William; Mercher, Thomas; Droin, Nathalie; Ogawa, Seishi; Nguyen-Khac, Florence; Bernard, Olivier A. (1 September 2014).
1167:
Zink, Florian; Stacey, Simon N.; Norddahl, Gudmundur L.; Frigge, Michael L.; Magnusson, Olafur T.; Jonsdottir, Ingileif; Thorgeirsson, Thorgeir E.; Sigurdsson, Asgeir; Gudjonsson, Sigurjon A. (2017-01-01).
2901:
Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev
Cardiol. 2018 Sep;15(9):505-522. doi: 10.1038/s41569-018-0064-2. PMID: 30065258; PMCID:
2387:
Steensma DP. Clinical consequences of clonal hematopoiesis of indeterminate potential. Blood Adv. 2018 Nov 27;2(22):3404-3410. doi: 10.1182/bloodadvances.2018020222. PMID: 30482770; PMCID: PMC6258914.
2931:/Bekele DI, Patnaik MM. Autoimmunity, Clonal Hematopoiesis, and Myeloid Neoplasms. Rheum Dis Clin North Am. 2020 Aug;46(3):429-444. doi: 10.1016/j.rdc.2020.03.001. Epub 2020 Jun 10. PMID: 32631598.
2956:
Tsai FD, Lindsley RC. Clonal hematopoiesis in the inherited bone marrow failure syndromes. Blood. 2020 Oct 1;136(14):1615-1622. doi: 10.1182/blood.2019000990. PMID: 32736377; PMCID: PMC7530647.
2171:
376:
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
1362:
Jaiswal, Siddhartha; Natarajan, Pradeep; Silver, Alexander J.; Gibson, Christopher J.; Bick, Alexander G.; Shvartz, Eugenia; McConkey, Marie; Gupta, Namrata; Gabriel, Stacey (2017-06-21).
2947:
Hall T, Gurbuxani S, Crispino JD. Malignant progression of preleukemic disorders. Blood. 2024 May 30;143(22):2245-2255. doi: 10.1182/blood.2023020817. PMID: 38498034; PMCID: PMC11181356.
1033:, Michael C.; McMichael, Joshua F.; Schmidt, Heather K.; Yellapantula, Venkata; Miller, Christopher A.; Ozenberger, Bradley A.; Welch, John S.; Link, Daniel C.; Walter, Matthew J.;
2614:
Weeks LD, Ebert BL. Causes and consequences of clonal hematopoiesis. Blood. 2023 Dec 28;142(26):2235-2246. doi: 10.1182/blood.2023022222. PMID: 37931207; PMCID: PMC10862247.
138:
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 (
2203:
Fabre MA, Vassiliou GS. The lifelong natural history of clonal hematopoiesis and its links to myeloid neoplasia. Blood. 2024;143(7):573-581. doi:10.1182/blood.2023019964
561:.. 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 (
509:
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.
2045:
Hudson, Thomas J.; Brown, Andrew M. K.; Yousif, Fouad; Trinh, Quang M.; Stein, Lincoln D.; Minden, Mark D.; Wang, Jean C. Y.; Dick, John E. (20 February 2014).
524:
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%
50:
over the stem/progenitor cells without these mutations. Alternatively, clonal hematopoiesis may arise without a driving mutation, through mechanisms such as
793:
Steensma, David P.; Bejar, Rafael; Jaiswal, Siddhartha; Lindsley, R. Coleman; Sekeres, Mikkael A.; Hasserjian, Robert P.; Ebert, Benjamin L. (2 July 2015).
2179:
1229:
Satoru; de Witte, Theo; Blijlevens, Nicole M. A.; Muus, Petra; Huls, Gerwin; van der
Reijden, Bert A.; Ogawa, Seishi; Jansen, Joop H. (21 April 2017).
502:
874:
Jennifer L.; Lander, Eric S.; Sullivan, Patrick F.; Sklar, Pamela; Grönberg, Henrik; Hultman, Christina M.; McCarroll, Steven A. (25 December 2014).
368:
publications and a large multi-cohort study published in 2017 appears to confirm the causal link between CHIP and cardiovascular disease in humans.
1920:
Jan, Max; Snyder, Thomas M.; Corces-Zimmerman, M. Ryan; Vyas, Paresh; Weissman, Irving L.; Quake, Stephen R.; Majeti, Ravindra (29 August 2012).
393:
by requiring increased proliferation to replenish immune cells. CHIP has been documented in people with HIV infection and autoimmune disease.
2922:
clonal hematopoiesis among older adults. Nat Med. 2021 Jun;27(6):1006-1011. doi: 10.1038/s41591-021-01357-y. Epub 2021 Jun 7. PMID: 34099923.
363:
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
389:, the low-level systemic inflammation implicated in age-related chronic illnesses. Aging and persistent inflammation both exhaust normal
67:
The first major evidence for the existence of prevalent clonal hematopoiesis in healthy people was put forth in the 1990s. Using the
2586:
605:
537:
CCUS has a much higher risk of progression to MDS/AML than CHIP. The most frequent CCUS mutations are in epigenetic regulators (
377:
2587:"Acute Myeloid Leukemia (AML) Number of New Cases and Deaths Per 100,000 People (All Races, Males and Females), Age-Adjusted"
139:
97:
2784:
Zhu, Yanfang Peipei; Hedrick, Catherine C.; Gaddis, Dalia E. (24 February 2017). "Hematopoietic stem cells gone rogue".
2567:
Montalban-Bravo, Guillermo; Garcia-Manero, Guillermo; List, Alan; Kantarjian, Hagop M.; Cortes, Jorge E. (1 June 2016).
1977:
Corces-Zimmerman, M. Ryan; Hong, Wan-Jen; Weissman, Irving L.; Medeiros, Bruno C.; Majeti, Ravindra (18 February 2014).
201:
287:
The risk of transformation to myeloid malignancy depends on the specific mutation and the size of the clone. Single
1765:"Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia"
145:
109:
1476:
Busque, L.; Mio, R.; Mattioli, J.; Brais, E.; Blais, N.; Lalonde, Y.; Maragh, M.; Gilliland, D. G. (1 July 1996).
1719:
Weissman, Irving (21 September 2005). "Stem cell research: paths to cancer therapies and regenerative medicine".
506:
134:
Number of people estimated to be affected by clonal hematopoiesis out of the total U.S. population, by age group.
472:
mutations cause Tatton-Brown-Rahman syndrome, characterized by larger body habitus and intellectual disability.
1302:"Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma"
59:. Patients with solid tumors or lymphoma and clonal hematopoiesis have been shown to have an inferior outcome.
1979:"Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission"
1672:"Clonal remissions in acute nonlymphocytic leukemia: evidence for a multistep pathogenesis of the malignancy"
1621:
Fialkow, P. J.; Singer, J. W.; Adamson, J. W.; Vaidya, K.; Dow, L. W.; Ochs, J.; Moohr, J. W. (1 June 1981).
449:
620:
437:
223:
advantage on its host or there is another favorable stem cell dynamic that there is a clonal expansion.
205:
experimental designs compels the use of a higher threshold to identify legitimate clonal hematopoiesis.
2721:"Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice"
92:
state of cells, the underlying genetic determinants of the clonal expansion remained to be uncovered.
1030:
512:
The acquisition of additional mutations can cause CHIP to transform into the related blood disorders
795:"Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes"
615:
513:
481:
390:
280:
2843:
Tall, Alan R.; Levine, Ross L. (2 March 2017). "Cardiovascular disease: Commonality with cancer".
2512:"Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis"
1639:
1622:
1109:"Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis"
600:
420:
syndromes carry a risk of myeloid malignancy, particularly when there are germ line mutations in
27:
1922:"Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia"
1420:
590:
517:
457:
85:
56:
284:
overall risk for developing a blood cancer, with only about 0.5-1.0% transformation per year.
2281:
Abkowitz, Janis L.; Catlin, Sandra N.; McCallie, Monica T.; Guttorp, Peter (1 October 2002).
1170:"Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly"
723:"The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia"
345:
38:. As the name suggests, this subpopulation in the blood is characterized by a shared unique
2852:
2793:
2732:
2229:
2218:"Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults"
2216:
Young, Andrew L.; Challen, Grant A.; Birmann, Brenda M.; Druley, Todd E. (22 August 2016).
2058:
1990:
1242:
130:
2687:"Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias".
2113:"Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis"
8:
2990:
2283:"Evidence that the number of hematopoietic stem cells per animal is conserved in mammals"
476:
417:
101:
2856:
2797:
2736:
2233:
2062:
1994:
1246:
2884:
2825:
2761:
2720:
2663:
2636:
2544:
2511:
2486:
2453:
2365:
2332:
2258:
2217:
2145:
2112:
2087:
2046:
2021:
1978:
1954:
1921:
1897:
1864:
1559:
1539:
1478:"Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age"
1453:
1396:
1363:
1334:
1301:
1271:
1230:
1202:
1169:
1133:
1108:
1083:
1051:"Age-related mutations associated with clonal hematopoietic expansion and malignancies"
1050:
993:
960:
908:
875:
827:
794:
755:
722:
698:
680:
663:
2594:
1029:
Xie, Mingchao; Lu, Charles; Wang, Jiayin; McLellan, Michael D.; Johnson, Kimberly J.;
2876:
2868:
2829:
2817:
2809:
2766:
2748:
2700:
2668:
2568:
2549:
2531:
2491:
2473:
2431:
2423:
2370:
2352:
2312:
2304:
2263:
2245:
2150:
2132:
2092:
2074:
2026:
2008:
1959:
1941:
1902:
1884:
1844:
1836:
1794:
1786:
1744:
1736:
1701:
1693:
1652:
1644:
1603:
1595:
1551:
1543:
1507:
1499:
1458:
1440:
1401:
1383:
1339:
1321:
1276:
1258:
1207:
1189:
1138:
1088:
1070:
1038:
998:
980:
913:
895:
832:
814:
760:
742:
703:
685:
1563:
2888:
2860:
2801:
2756:
2740:
2692:
2658:
2648:
2539:
2523:
2481:
2465:
2413:
2360:
2344:
2294:
2253:
2237:
2140:
2124:
2082:
2066:
2016:
1998:
1949:
1933:
1892:
1876:
1826:
1776:
1728:
1683:
1634:
1587:
1535:
1489:
1448:
1432:
1391:
1375:
1329:
1313:
1266:
1250:
1197:
1181:
1128:
1120:
1078:
1062:
988:
972:
903:
887:
822:
806:
750:
734:
693:
675:
333:
81:
1688:
1671:
2527:
1937:
1880:
1863:
Neal; Tallman, Martin S.; Park, Christopher Y.; Abdel-Wahab, Omar (28 May 2014).
1831:
1814:
1436:
1185:
1124:
810:
31:
2696:
1591:
2995:
2653:
2348:
2299:
2282:
1983:
Proceedings of the
National Academy of Sciences of the United States of America
1042:
595:
527:
Persistent cytopenia (≥ 4 months) in one or more peripheral blood cell lineages
501:
Clonal hematopoiesis is sometimes compared to the unrelated blood disorders of
465:
157:
72:
47:
2637:"Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure"
2469:
2047:"Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia"
1865:"Hematopoietic stem cell origin of BRAFV600E mutations in hairy cell leukemia"
1781:
1764:
1494:
1477:
2984:
2872:
2813:
2752:
2535:
2477:
2427:
2356:
2308:
2249:
2136:
2078:
2012:
1945:
1888:
1840:
1790:
1740:
1732:
1697:
1648:
1599:
1547:
1503:
1444:
1387:
1325:
1317:
1262:
1227:
1193:
1074:
1034:
984:
899:
876:"Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence"
818:
746:
689:
398:
353:
51:
2805:
2744:
2003:
1815:"Acquired initiating mutations in early hematopoietic cells of CLL patients"
291:
mutations have the lowest risk of progression, while splicing factor genes,
2880:
2821:
2770:
2719:
Hirschi, Karen K.; Martin, Kathleen A.; Walsh, Kenneth (24 February 2017).
2704:
2672:
2553:
2495:
2435:
2374:
2316:
2267:
2154:
2096:
2030:
1963:
1906:
1848:
1798:
1748:
1462:
1405:
1343:
1280:
1211:
1142:
1092:
1002:
917:
836:
764:
707:
410:
386:
321:
317:
196:
and splicing gene mutations are more prevalent in those over 75 years old.
76:
68:
2566:
1705:
1656:
1555:
1511:
1379:
976:
891:
1607:
1364:"Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease"
738:
456:
mutation may lead to myeloid hyperproliferation; telomeropathies such as
329:
163:
89:
2864:
2241:
2070:
1254:
2418:
2401:
1524:
610:
520:. Clonal Cytopenias of Undetermined Significance (CCUS) is defined as:
394:
357:
35:
34:
contribute to the formation of a genetically distinct subpopulation of
721:
Sperling, Adam S.; Gibson, Christopher J.; Ebert, Benjamin L. (2017).
402:
344:
A second area of health that may be affected by CHIP is the risk for
259:
255:
2128:
1976:
1066:
662:
Jan, Max; Ebert, Benjamin L.; Jaiswal, Siddhartha (1 January 2017).
961:"Age-related clonal hematopoiesis associated with adverse outcomes"
406:
381:
39:
2111:
Cameron W.; Abdel-Wahab, Omar; Levine, Ross L. (1 November 2012).
1623:"Acute nonlymphocytic leukemia: heterogeneity of stem cell origin"
2333:"The origin and evolution of mutations in acute myeloid leukemia"
1046:
957:
484:. The mutated stem cells then acquire a self-renewal advantage.
2717:
2109:
2685:
2452:
Heuser, Michael; Thol, Felicitas; Ganser, Arnold (6 May 2016).
2402:"Universal patterns of stem cell fate in cycling adult tissues"
1670:
Fialkow, P. J.; Janssen, J. W.; Bartram, C. R. (1 April 1991).
872:
566:
538:
533:
All other causes of cytopenia and molecular aberration excluded
469:
349:
325:
288:
189:
2591:
NIH Surveillance, Epidemiology, and End
Results Program (SEER)
1761:
2280:
1919:
1298:
578:
574:
558:
550:
546:
453:
433:
429:
425:
421:
312:
184:
168:
152:
1361:
792:
562:
554:
542:
461:
441:
308:
304:
300:
296:
292:
219:
193:
178:
2166:
2164:
1620:
1576:
2215:
570:
503:
monoclonal gammopathy of undetermined significance (MGUS)
445:
436:, or SAMD9/9L. Examples include ribosomopathies such as
43:
2633:
2508:
1811:
1166:
1105:
262:
or immature "blast" cells in the bone marrow) as having
2161:
2043:
1475:
1223:
1221:
264:
Clonal Hematopoiesis of Indeterminate Potential (CHIP)
1970:
1669:
530:
Diagnostic criteria of myeloid neoplasm not fulfilled
2560:
2400:Klein, Allon M.; Simons, Benjamin D. (2011-08-01).
1218:
720:
2329:
239:
2934:
2454:"Clonal Hematopoiesis of Indeterminate Potential"
1861:
1028:
2982:
2943:
2941:
2939:
2937:
2783:
2451:
868:
866:
248:
26:, is a common aging-related phenomenon in which
1231:"Clonal evolution in myelodysplastic syndromes"
953:
951:
949:
947:
864:
862:
860:
858:
856:
854:
852:
850:
848:
846:
788:
786:
784:
782:
780:
778:
776:
774:
661:
20:Clonal hematopoiesis of indeterminate potential
2502:
2447:
2445:
1755:
1294:
1292:
1290:
945:
943:
941:
939:
937:
935:
933:
931:
929:
927:
254:gene but without evidence of disease (such as
2641:Journal of the American College of Cardiology
2274:
2211:
2209:
1712:
1518:
226:
1663:
1640:10.1182/blood.V57.6.1068.bloodjournal5761068
1614:
1570:
1037:, Elaine R.; Dipersio, John F.; Chen, Feng;
843:
771:
714:
71:, scientists found that there was nonrandom
2711:
2442:
2399:
2103:
2037:
1469:
1287:
924:
657:
655:
413:as it relates to hematologic malignancies.
378:autologous stem cell transplantation (ASCT)
2842:
2323:
2206:
1855:
1419:Park, Soo J.; Bejar, Rafael (2020-03-01).
1024:
1022:
1020:
1018:
1016:
1014:
1012:
653:
651:
649:
647:
645:
643:
641:
639:
637:
635:
409:pathway are all thought to play a role in
176:), or members of the DNA damage response (
2836:
2760:
2662:
2652:
2579:
2543:
2485:
2417:
2364:
2298:
2257:
2144:
2086:
2020:
2002:
1953:
1896:
1830:
1805:
1780:
1687:
1638:
1493:
1452:
1418:
1395:
1333:
1270:
1201:
1132:
1082:
992:
907:
826:
754:
697:
679:
2777:
2199:
2197:
1913:
1718:
129:
1009:
632:
606:Hematopoietic stem cell transplantation
496:
192:is the most prevalent driver mutation,
2983:
339:
121:
88:. As the HUMARA assay is based on the
2510:Vassiliou, George S. (3 March 2015).
2395:
2393:
2194:
1357:
1355:
1353:
507:monoclonal B-cell lymphocytosis (MBL)
1162:
1160:
1158:
1156:
1154:
1152:
273:
1580:The New England Journal of Medicine
965:The New England Journal of Medicine
880:The New England Journal of Medicine
13:
2458:Deutsches Ärzteblatt International
2390:
1540:10.1046/j.1365-2141.1997.1933010.x
1350:
681:10.1053/j.seminhematol.2016.10.002
98:chronic lymphocytic leukemia (CLL)
14:
3007:
1149:
1421:"Clonal hematopoiesis in cancer"
371:
2968:
2959:
2950:
2925:
2915:
2905:
2895:
2679:
2627:
2617:
2608:
2381:
2172:"American FactFinder - Results"
1412:
1368:New England Journal of Medicine
460:with acquired mutations in the
380:as part of their treatment for
240:Non-candidate-driver mechanisms
28:hematopoietic stem cells (HSCs)
1926:Science Translational Medicine
1869:Science Translational Medicine
1528:British Journal of Haematology
1099:
281:myelodysplastic syndrome (MDS)
1:
1689:10.1182/blood.V77.7.1415.1415
626:
573:) and transcription factors (
450:Severe Congenital Neutropenia
249:Implications for human health
2528:10.1016/j.celrep.2015.02.005
1938:10.1126/scitranslmed.3004315
1881:10.1126/scitranslmed.3008004
1832:10.1158/2159-8290.CD-14-0104
1437:10.1016/j.exphem.2020.02.001
1306:Journal of Clinical Oncology
1186:10.1182/blood-2017-02-769869
1125:10.1016/j.celrep.2015.02.005
811:10.1182/blood-2015-03-631747
487:
86:acute myeloid leukemia (AML)
7:
2569:"Myelodysplastic Syndromes"
1592:10.1056/NEJM197907053010101
1180:(6): blood–2017–02–769869.
621:Myeloproliferative neoplasm
584:
438:Schwachman-Diamond syndrome
10:
3012:
2654:10.1016/j.jacc.2021.04.085
2349:10.1016/j.cell.2012.06.023
2300:10.1182/blood-2002-03-0822
227:Candidate driver mutations
212:
62:
2697:10.1093/eurheartj/ehad670
2470:10.3238/arztebl.2016.0317
1782:10.1016/j.ccr.2011.06.029
1495:10.1182/blood.V88.1.59.59
581:) occur as a late event.
549:), RNA splicing factors (
324:(RDW ≥ 15%), cytopenias (
102:hairy cell leukemia (HCL)
1733:10.1001/jama.294.11.1359
1318:10.1200/JCO.2016.71.6712
1049:, Li (1 December 2014).
616:Myelodysplastic syndrome
482:Hematopoietic stem cells
440:, in which mutations in
391:hematopoietic stem cells
16:Expansion of blood cells
2806:10.1126/science.aam7939
2745:10.1126/science.aag1381
2004:10.1073/pnas.1324297111
1425:Experimental Hematology
601:Hematopoietic stem cell
156:), signaling proteins (
2689:European Heart Journal
668:Seminars in Hematology
664:"Clonal hematopoiesis"
591:Acute myeloid leukemia
458:dyskeratosis congenita
336:) and age ≥ 65 years.
135:
57:cardiovascular disease
2573:www.cancernetwork.com
2222:Nature Communications
2176:factfinder.census.gov
1380:10.1056/NEJMoa1701719
1235:Nature Communications
977:10.1056/NEJMoa1408617
892:10.1056/NEJMoa1409405
727:Nature Reviews Cancer
444:may lead to aberrant
133:
30:or other early blood
739:10.1038/nrc.2016.112
497:Associated disorders
2865:10.1038/nature21505
2857:2017Natur.543...45T
2798:2017Sci...355..798Z
2737:2017Sci...355..842F
2242:10.1038/ncomms12484
2234:2016NatCo...712484Y
2182:on 14 February 2020
2071:10.1038/nature13038
2063:2014Natur.506..328S
1995:2014PNAS..111.2548C
1255:10.1038/ncomms15099
1247:2017NatCo...815099D
477:bone marrow failure
418:bone marrow failure
340:Cardiovascular risk
202:digital droplet PCR
122:Population genetics
2419:10.1242/dev.060103
136:
2792:(6327): 798–799.
2731:(6327): 842–847.
2412:(15): 3103–3111.
2123:(11): 1179–1181.
2057:(7488): 328–333.
1932:(149): 149ra118.
1727:(11): 1359–1366.
1312:(14): 1598–1605.
1061:(12): 1472–1478.
971:(26): 2488–2498.
886:(26): 2477–2487.
274:Blood cancer risk
3003:
2976:
2972:
2966:
2963:
2957:
2954:
2948:
2945:
2932:
2929:
2923:
2919:
2913:
2909:
2903:
2899:
2893:
2892:
2840:
2834:
2833:
2781:
2775:
2774:
2764:
2715:
2709:
2708:
2683:
2677:
2676:
2666:
2656:
2631:
2625:
2621:
2615:
2612:
2606:
2605:
2603:
2602:
2593:. Archived from
2583:
2577:
2576:
2564:
2558:
2557:
2547:
2522:(8): 1239–1245.
2506:
2500:
2499:
2489:
2449:
2440:
2439:
2421:
2397:
2388:
2385:
2379:
2378:
2368:
2327:
2321:
2320:
2302:
2293:(7): 2665–2667.
2278:
2272:
2271:
2261:
2213:
2204:
2201:
2192:
2191:
2189:
2187:
2178:. Archived from
2168:
2159:
2158:
2148:
2107:
2101:
2100:
2090:
2041:
2035:
2034:
2024:
2006:
1989:(7): 2548–2553.
1974:
1968:
1967:
1957:
1917:
1911:
1910:
1900:
1875:(238): 238ra71.
1859:
1853:
1852:
1834:
1825:(9): 1088–1101.
1819:Cancer Discovery
1809:
1803:
1802:
1784:
1759:
1753:
1752:
1716:
1710:
1709:
1691:
1682:(7): 1415–1417.
1667:
1661:
1660:
1642:
1633:(6): 1068–1073.
1618:
1612:
1611:
1574:
1568:
1567:
1522:
1516:
1515:
1497:
1473:
1467:
1466:
1456:
1416:
1410:
1409:
1399:
1359:
1348:
1347:
1337:
1296:
1285:
1284:
1274:
1225:
1216:
1215:
1205:
1164:
1147:
1146:
1136:
1103:
1097:
1096:
1086:
1026:
1007:
1006:
996:
955:
922:
921:
911:
870:
841:
840:
830:
790:
769:
768:
758:
718:
712:
711:
701:
683:
659:
334:thrombocytopenia
82:clonal expansion
32:cell progenitors
3011:
3010:
3006:
3005:
3004:
3002:
3001:
3000:
2981:
2980:
2979:
2973:
2969:
2964:
2960:
2955:
2951:
2946:
2935:
2930:
2926:
2920:
2916:
2910:
2906:
2900:
2896:
2851:(7643): 45–47.
2841:
2837:
2782:
2778:
2716:
2712:
2684:
2680:
2635:(6 July 2021).
2632:
2628:
2622:
2618:
2613:
2609:
2600:
2598:
2585:
2584:
2580:
2565:
2561:
2507:
2503:
2464:(18): 317–322.
2450:
2443:
2398:
2391:
2386:
2382:
2328:
2324:
2279:
2275:
2214:
2207:
2202:
2195:
2185:
2183:
2170:
2169:
2162:
2129:10.1038/ng.2413
2117:Nature Genetics
2108:
2104:
2042:
2038:
1975:
1971:
1918:
1914:
1860:
1856:
1810:
1806:
1760:
1756:
1717:
1713:
1668:
1664:
1619:
1615:
1575:
1571:
1523:
1519:
1474:
1470:
1417:
1413:
1360:
1351:
1297:
1288:
1226:
1219:
1165:
1150:
1104:
1100:
1067:10.1038/nm.3733
1055:Nature Medicine
1027:
1010:
956:
925:
871:
844:
791:
772:
719:
715:
660:
633:
629:
587:
499:
490:
374:
342:
320:(MCV ≥100 fL),
276:
251:
242:
229:
215:
124:
65:
17:
12:
11:
5:
3009:
2999:
2998:
2993:
2978:
2977:
2967:
2958:
2949:
2933:
2924:
2914:
2904:
2894:
2835:
2776:
2710:
2678:
2626:
2616:
2607:
2578:
2559:
2501:
2441:
2389:
2380:
2343:(2): 264–278.
2322:
2273:
2205:
2193:
2160:
2102:
2036:
1969:
1912:
1854:
1804:
1775:(2): 246–259.
1754:
1711:
1662:
1613:
1569:
1534:(4): 920–926.
1517:
1468:
1411:
1374:(2): 111–121.
1349:
1286:
1217:
1148:
1119:(8): 1239–45.
1098:
1045:, Timothy J.;
1041:, Richard K.;
1008:
923:
842:
770:
713:
630:
628:
625:
624:
623:
618:
613:
608:
603:
598:
596:Haematopoiesis
593:
586:
583:
535:
534:
531:
528:
525:
498:
495:
489:
486:
466:Fanconi anemia
464:promoter, and
373:
370:
341:
338:
275:
272:
250:
247:
241:
238:
228:
225:
214:
211:
123:
120:
73:X-inactivation
64:
61:
42:in the cells'
15:
9:
6:
4:
3:
2:
3008:
2997:
2994:
2992:
2989:
2988:
2986:
2971:
2962:
2953:
2944:
2942:
2940:
2938:
2928:
2918:
2908:
2898:
2890:
2886:
2882:
2878:
2874:
2870:
2866:
2862:
2858:
2854:
2850:
2846:
2839:
2831:
2827:
2823:
2819:
2815:
2811:
2807:
2803:
2799:
2795:
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468:. Inherited
448:activation;
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411:inflammaging
387:inflammaging
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356:and cardiac
346:heart attack
343:
322:anisocytosis
318:macrocytosis
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77:X chromosome
69:HUMARA assay
66:
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2902:PMC6146930.
2406:Development
1769:Cancer Cell
1431:: 105–112.
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452:, in which
395:Interferons
358:arrhythmias
330:neutropenia
164:spliceosome
104:, and AML.
36:blood cells
2991:Hematology
2985:Categories
2601:2017-05-01
1586:(1): 1–5.
627:References
611:Hematology
553:, SRSF2),
493:findings.
475:Inherited
416:Inherited
90:epigenetic
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2873:1476-4687
2830:206657434
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585:See also
407:TGF-beta
405:and the
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2853:Bibcode
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2733:Bibcode
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2259:4996934
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1676:Blood
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1031:Wendl
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579:RUNX1
575:CEBPA
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551:SF3B1
547:ASXL1
454:CSF3R
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430:GATA2
426:DDX41
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