OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press100310.17650/1818-8346-2025-20-1-28-54NEW DIRECTIONS, DIAGNOSTIC OPPORTUNITIES, AND TREATMENT ADVANCESНОВЫЕ НАПРАВЛЕНИЯ, ВОЗМОЖНОСТИ ДИАГНОСТИКИ И УСПЕХИ ЛЕЧЕНИЯThe phenomenon of clonal hematopoiesis: etiology, classification and its prognostic roleФеномен клонального гемопоэза: этиология, классификация и прогностическая рольhttps://orcid.org/0000-0002-1706-6642KunevichE. O.КуневичЕ. О.
Russian Federation

Evgeniy Olegovich Kunevich

194291;  lit. A, Build. 1, 45 Lunacharskogo Prospekt; Saint Petersburg

Евгений Олегович Куневич

194291; пр-кт Луначарского, 45; Санкт-Петербург

kunevich17@gmail.comhttps://orcid.org/0000-0002-2135-2051MikhalevaM. A.МихалеваМ. А.
Russian Federation

191024; 16 2nd Sovetskaya St.; Saint Petersburg

191024; ул. 2-я Советская, 16; Санкт-Петербург

https://orcid.org/0000-0002-5083-915XKrysyukO. B.КрысюкО. Б.
Russian Federation

191024; 16 2nd Sovetskaya St.; 199034; 7–9 Universitetskaya Naberezhnaya; Saint Petersburg

191024; ул. 2-я Советская, 16; 199034; Университетскаянабережная, 7–9; Санкт-Петербург

https://orcid.org/0000-0003-1964-3690BogdanovA. N.БогдановА. Н.
Russian Federation

199034; 7–9 Universitetskaya Naberezhnaya; Saint Petersburg; 197706; 9 Borisova St.; Saint Petersburg; Sestroretsk 

199034; Университетская набережная, 7–9; Санкт-Петербург; 197706; ул. Борисова, 9; Санкт-Петербург; Сестрорецк

https://orcid.org/0000-0001-9260-3025ZhernyakovaA. A.ЖерняковаА. А.
Russian Federation

191024; 16 2nd Sovetskaya St.; Saint Petersburg

191024; ул. 2-я Советская, 16; Санкт-Петербург

https://orcid.org/0000-0003-1784-0375VoloshinS. V.ВолошинС. В.
Russian Federation

194291;  lit. A, Build. 1, 45 Lunacharskogo Prospekt; 194044; 6 Akademika Lebedeva St.; Saint Petersburg

194291; пр-кт Луначарского, 45; 194044; ул. Академика Лебедева, 6; Санкт-Петербург

Leningrad Regional Clinical HospitalГБУЗ «Ленинградская областная клиническая больница»Russian Research Institute of Hematology and Transfusiology, Federal Medical and Biological AgencyФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико- биологического агентства»Saint-Petersburg State UniversityФГБОУ ВО «Санкт-Петербургский государственный университет»City hospital No. 40СПб ГБУЗ «Городская больница № 40 Курортного района»Military Medical Academy named after S. M. Kirov, Ministry of Defense of RussiaФГБВОУ ВО «Военно-медицинская академия им. С. М. Кирова» Минобороны России1903202520128542003202520032025https://oncohematology.abvpress.ru/ongm/article/view/1003

   The phenomenon of clonal hematopoiesis (CH) has been the subject of intensive research since 2014, facilitated by the development of high‑throughput sequencing technology. with age, the prevalence of CH increases, which is associated with an increased risk of hematological and cardiovascular diseases, as well as with overall mortality. The occurrence of somatic mutations in hematopoietic stem cells is the primary mechanism of CH, as a result of which the balance between cell division and differentiation is disrupted, which leads to the expansion of cell clones with specific genetic changes. The article reviews the concept of CH and its various types, including clonal hematopoiesis of indeterminate and tumorigenic potential, as well as associated conditions such as idiopathic cytopenia of undetermined significance, clonal cytopenia of undetermined significance, and idiopathic dysplasia of undetermined significance. Clonal hematopoiesis is defined by the presence of somatic mutations in myeloid‑related genes (commonly DNMT3A, TET2, and ASXL1) in hematopoietic cells, which can be present in both healthy people and patients with hematological neoplasia. The importance of distinguishing between different CH forms depending on their prognostic significance and the potential risk of transformation into malignant neoplasms is emphasized. Mutations associated with CH may increase the risk of cardiovascular diseases, type 2 diabetes mellitus, chronic obstructive pulmonary disease, venous thrombosis, and myeloid and lymphoid neoplasms. In conclusion, the need to develop formalized diagnostic criteria and predictive models for risk stratification in individuals with various CH forms is emphasized, which can significantly affect diagnostic approaches and the possibility of treating these conditions.

   Феномен клонального гемопоэза (КГ) стал объектом интенсивных исследований с 2014 г., чему способствовало развитие технологии высокопроизводительного секвенирования. С возрастом увеличивается распространенность КГ, который связан с повышенным риском онкогематологических и сердечно‑сосудистых заболеваний, а также общей летальностью. Возникновение соматических мутаций в гемопоэтических стволовых клетках является основным механизмом КГ, в результате которого нарушается баланс между клеточным делением и дифференцировкой, что приводит к экспансии клонов клеток с определенными генетическими изменениями. В статье рассматривается понятие КГ и его различных форм, включая КГ неопределенного и онкогенного потенциала, а также связанные состояния, такие как идиопатическая цитопения неопределенного значения, клональная цитопения неопределенного значения и идиопатическая дисплазия неопределенного значения. КГ определяют при наличии соматических мутаций в генах миелоидной направленности (наиболее часто – DNMT3A, TET2 и ASXL1) в кроветворных клетках, которые могут присутствовать как у здоровых людей, так и у пациентов с гематологическими неоплазиями. Подчеркнута важность разграничения различных форм КГ в зависимости от их прогностической значимости и потенциального риска трансформации в злокачественные новообразования. Мутации, связанные с КГ, могут увеличивать риск сердечно‑сосудистых заболеваний, сахарного диабета 2‑го типа, хронической обструктивной болезни легких, венозных тромбозов, а также миелоидных и лимфоидных новообразований. Отмечена необходимость разработки формализованных диагностических критериев и прогностических моделей для стратификации риска у лиц с различными формами КГ, что может значительно повлиять на подходы к диагностике и возможность терапии данных состояний.

clonal hematopoiesiscytopeniavariant allele frequencysequencingnext generation sequencingx‑chromosome inactivationstem cellmyelodysplastic syndromemalignancyagingклональный гемопоэзцитопениячастота вариантного аллелясеквенированиесеквенирование нового поколенияинактивация х‑хромосомыстволовая клеткамиелодиспластический синдромзлокачественное новообразованиестарениеThe work was performed without external fundingРабота выполнена без спонсорской поддержкиLyon M.F. Sex chromatin and gene action in the mammalian X­chromosome. Am J Hum Genet 1962;14:135–48.Beutler E., Yeh M., Fairbanks V.F. The normal human female as a mosaic of X­chromosome activity: studies using the gene for C­6­PD­deficiency as a marker. Proc Natl Acad Sci USA 1962;48(1):9–16. DOI: 10.1073/pnas.48.1.9Xie M., Lu C., Wang J. et al. Age­related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014;20(12):1472–8. DOI: 10.1038/nm.3733Genovese G., Kähler A.K., Handsaker R.E. et al. Clonal hematopoiesis and blood­cancer risk inferred from blood DNA sequence. N Engl J Med 2014;371(26):2477–87. DOI: 10.1056/NEJMoa1409405Jaiswal S., Fontanillas P., Flannick J. et al. Age­related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014;371(26):2488–98. DOI: 10.1056/NEJMoa1408617Knudson A.G. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820–3. DOI: 10.1073/pnas.68.4.820Vogelstein B., Papadopoulos N., Velculescu V.E. et al. Cancer genome landscapes. Science 2013;339:1546–58. DOI: 10.1126/science.1235122Lee­Six H., Øbro N.F., Shepherd M.S. et al. Population dynamics of normal human blood inferred from somatic mutations. Nature 2018;561:473–8. DOI: 10.1038/s41586­018­0497­0Filipek­Gorzała J., Kwiecińska P., Szade A., Szade K. The dark side of stemness – the role of hematopoietic stem cells in development of blood malignancies. Front Oncol 2024;14:1308709. DOI: 10.3389/fonc.2024.1308709Nakamura­Ishizu A., Takizawa H., Suda T. The analysis, roles and regulation of quiescence in hematopoietic stem cells. Development 2014;141(24):4656–66. DOI: 10.1242/dev.106575Loeffler D., Schneiter F., Wang W. et al. Asymmetric organelle inheritance predicts human blood stem cell fate. Blood 2022;139(13):2011–23. DOI: 10.1182/blood.2020009778Loeffler D., Schroeder T. Symmetric and asymmetric activation of hematopoietic stem cells. Curr Opin Hematol 2021;28(4):262–8. DOI: 10.1097/MOH.0000000000000644Mitchell E., Spencer Chapman M., Williams N. et al. Clonal dynamics of haematopoiesis across the human lifespan. Nature 2022;606(7913):343–50. DOI: 10.1038/s41586­022­04786­yWelch J.S., Ley T.J., Link D.C. et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012;150(2):264–78. DOI: 10.1016/j.cell.2012.06.023Bowman R.L., Busque L., Levine R.L. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 2018;22:157–70. DOI: 10.1016/j.stem.2018.01.011Steensma D.P., Bejar R., Jaiswal S. et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015;126(1):9–16. DOI: 10.1182/blood­2015­03­631747Steensma D.P. Clinical implications of clonal hematopoiesis. Mayo Clin Proc 2018;93:1122–30. DOI: 10.1016/j.mayocp.2018.04.002Coombs C.C., Zehir A., Devlin S.M. et al. Therapy­related clonal hematopoiesis in patients with non­hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 2017;21(3):374–82.e4. DOI: 10.1016/j.stem.2017.07.010Giani A.M., Gallo G.R., Gianfranceschi L., Formenti G. Long walk to genomics: history and current approaches to genome sequencing and assembly. Comput Struct Biotechnol J 2019;18: 9–19. DOI: 10.1016/j.csbj.2019.11.002Chen E.Y., Tan C.M., Kou Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 2013;14:128. DOI: 10.1186/1471­2105­14­128Kuleshov M.V., Jones M.R., Rouillard A.D. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 2016;44(W1):W90–7. DOI: 10.1093/nar/gkw377Xie Z., Bailey A., Kuleshov M.V. et al. Gene set knowledge discovery with Enrichr. Curr Protoc 2021;1(3):e90. DOI: 10.1002/cpz1.90Linder D., Gartler S.M. Glucose­6­phosphate dehydrogenase mosaicism: utilization as a cell marker in the study of leiomyomas. Science 1965;150(3692):67–9. DOI: 10.1126/science.150.3692.67Rowley J.D. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290–3. DOI: 10.1038/243290a0Fialkow P.J. The origin and development of human tumors studied with cell markers. N Engl J Med 1974;291(1):26–35. DOI: 10.1056/NEJM197407042910109Busque L., Gilliland D.G. X­inactivation analysis in the 1990s: promise and potential problems. Leukemia 1998;12(2):128–35. DOI: 10.1038/sj.leu.2400936Ayachi S., Buscarlet M., Busque L. 60 Years of clonal hematopoiesis research: from X­chromosome inactivation studies to the identification of driver mutations. Exp Hematol 2020;83:2–11. DOI: 10.1016/j.exphem.2020.01.008Vogelstein B., Fearon E.R., Hamilton S.R., Feinberg A.P. Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors. Science 1985;227(4687):642–5. DOI: 10.1126/science.2982210Gilliland D.G., Blanchard K.L., Levy J. et al. Clonality in myeloproliferative disorders: analysis by means of the polymerase chain reaction. Proc Natl Acad Sci USA 1991;88(15):6848–52. DOI: 10.1073/pnas.88.15.6848Prchal J.T., Guan Y.L. A novel clonality assay based on transcriptional analysis of the active X chromosome. Stem Cells 1993;11(Suppl 1):62–5. DOI: 10.1002/stem.5530110613Luhovy M., Liu Y., Belickova M. et al. A novel clonality assay based on transcriptional polymorphism of X chromosome gene p55. Biol Blood Marrow Transplant 1995;1(2):81–7.Fey M.F., Peter H.J., Hinds H.L. et al. Clonal analysis of human tumors with M27 beta, a highly informative polymorphic X chromosomal probe. J Clin Invest 1992;89(5):1438–44. DOI: 10.1172/JCI115733Fey M.F., Liechti­Gallati S., von Rohr A. et al. Clonality and X­inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe. Blood 1994;83(4):931–8.Busque L., Mio R., Mattioli J. et al. Nonrandom X­inactivation patterns in normal females: lyonization ratios vary with age. Blood 1996;88(1):59–65.Sandovici I., Naumova A.K., Leppert M. et al. A longitudinal study of X­inactivation ratio in human females. Hum Genet 2004;115(5):387–92. DOI: 10.1007/s00439­004­1177­8Kristiansen M., Knudsen G.P., Bathum L. et al. Twin study of genetic and aging effects on X chromosome inactivation. Eur J Hum Genet 2005;13(5):599–606. DOI: 10.1038/sj.ejhg.5201398Busque L., Patel J.P., Figueroa M.E. et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 2012;44(11):1179–81. DOI: 10.1038/ng.2413Testa U., Castelli G., Pelosi E. Clonal hematopoiesis: role in hematologic and non­hematologic malignancies. Mediterr J Hematol Infect Dis 2022;14(1):e2022069. DOI: 10.4084/MJHID.2022.069Laurie C.C., Laurie C.A., Rice K. et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet 2012;44(6):642–50. DOI: 10.1038/ng.2271Jaiswal S., Ebert B.L. Clonal hematopoiesis in human aging and disease. Science 2019;366(6465):eaan4673. DOI: 10.1126/science.aan4673Zink F., Stacey S.N., Norddahl G.L. et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 2017;130(6):742–52. DOI: 10.1182/blood­2017­02­769869Young A.L., Challen G.A., Birmann B.M., Druley T.E. Clonal haematopoiesis harbouring AML­associated mutations is ubiquitous in healthy adults. Nat Commun 2016;7:12484. DOI: 10.1038/ncomms12484Abelson S., Collord G., Ng S.W.K. et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 2018;559:400–4. DOI: 10.1038/s41586­018­0317­6Wong W.H., Tong R.S., Young A.L., Druley T.E. Rare event detection using error­corrected DNA and RNA sequencing. J Vis Exp 2018;(138):57509. DOI: 10.3791/57509Shlush L.I. Age­related clonal hematopoiesis. Blood 2018;131(5):496–504. DOI: 10.1182/blood­2017­07­746453De Haan G., Lazare S.S. Aging of hematopoietic stem cells. Blood 2018;131(5):479–87. DOI: 10.1182/blood­2017­06­746412Challen G.A., Sun D., Jeong M. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 2011;44(1):23–31. DOI: 10.1038/ng.1009Jeong M., Park H.J., Celik H. et al. Loss of Dnmt3a immortalizes hematopoietic stem cells in vivo. Cell Rep 2018;23(1):1–10. DOI: 10.1016/j.celrep.2018.03.025Moran­Crusio K., Reavie L., Shih A. et al. Tet2 loss leads to increased hematopoietic stem cell self­renewal and myeloid transformation. Cancer Cell 2011;20(1):11–24. DOI: 10.1016/j.ccr.2011.06.001Quivoron C., Couronné L., Valle D.V. et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 2011;20(1):25–38. DOI: 10.1016/j.ccr.2011.06.003Jones A.V., Chase A., Silver R.T. et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet 2009;41(4):446–9. DOI: 10.1038/ng.334Kilpivaara O., Mukherjee S., Schram A.M. et al. A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)­positive myeloproliferative neoplasms. Nat Genet 2009;41(4):455–9. DOI: 10.1038/ng.342Vas V., Senger K., Dörr K. et al. Aging of the microenvironment influences clonality in hematopoiesis. PLoS One 2012;7(8):e42080. DOI: 10.1371/journal.pone.0042080Bick A.G., Weinstock J.S., Nandakumar S.K. et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 2020;586(7831):763–8. DOI: 10.1038/s41586­020­2819­2Cook E.K., Izukawa T., Young S. et al. Comorbid and inflammatory characteristics of genetic subtypes of clonal hematopoiesis. Blood Adv 2019;3(16):2482–6. DOI: 10.1182/bloodadvances.2018024729Jaiswal S., Natarajan P., Silver A.J. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 2017;377(2):111–21. DOI: 10.1056/NEJMoa1701719Busque L., Sun M., Buscarlet M. et al. High­sensitivity C­reactive protein is associated with clonal hematopoiesis of indeterminate potential. Blood Adv 2020;4(11):2430–8. DOI: 10.1182/bloodadvances.2019000770SanMiguel J.M., Loberg M., Heuer S. et al. Cell­extrinsic stressors from the aging bone marrow (BM) microenvironment promote Dnmt3a­mutant clonal hematopoiesis. Blood 2019;134(Suppl 1):5. DOI: 10.1182/blood­2019­124511Wong T.N., Ramsingh G., Young A.L. et al. Role of TP53 mutations in the origin and evolution of therapy­related acute myeloid leukaemia. Nature 2015;518(7540):552–5. DOI: 10.1038/nature13968Lindsley R.C., Saber W., Mar B.G. et al. Prognostic mutations in myelodysplastic syndrome after stem­cell transplantation. N Engl J Med 2017;376(6):536–47. DOI: 10.1056/NEJMoa1611604Swisher E.M., Harrell M.I., Norquist B.M. et al. Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. JAMA Oncol 2016;2(3):370–2. DOI: 10.1001/jamaoncol.2015.6053Zajkowicz A., Butkiewicz D., Drosik A. et al. Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients. Br J Cancer 2015;112(6):1114–20. DOI: 10.1038/bjc.2015.79Ruark E., Snape K., Humburg P. et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 2013;493(7432):406–10. DOI: 10.1038/nature11725Cardoso M., Paulo P., Maia S., Teixeira M.R. Truncating and missense PPM1D mutations in early­onset and/or familial/hereditary prostate cancer patients. Genes Chromosomes Cancer 2016;55(12):954–61. DOI: 10.1002/gcc.22393Singh A., Balasubramanian S. The crossroads of cancer therapies and clonal hematopoiesis. Semin Hematol 2024;61(1):16–21. DOI: 10.1053/j.seminhematol.2024.01.006Zhang Y., Yao Y., Xu Y. et al. Pan­cancer circulating tumor DNA detection in over 10,000 Chinese patients. Nat Commun 2021;12(1):11. DOI: 10.1038/s41467­020­20162­8Bolton K.L., Ptashkin R.N., Gao T. et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat Genet 2020;52:1219–26. DOI: 10.1038/s41588­020­00710­0Cooper J.N., Young N.S. Clonality in context: hematopoietic clones in their marrow environment. Blood 2017;130(22):2363–72. DOI: 10.1182/blood­2017­07­794362Gondek L.P. CHIP: is clonal hematopoiesis a surrogate for aging and other disease? Hematology Am Soc Hematol Educ Program 2021;2021(1):384–9. DOI: 10.1182/hematology.2021000270Yoshizato T., Dumitriu B., Hosokawa K. et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med 2015;373(1):35–47. DOI: 10.1056/NEJMoa1414799Finkel T., Serrano M., Blasco M.A. The common biology of cancer and ageing. Nature 2007;448(7155):767–74. DOI: 10.1038/nature05985López­Otín C., Blasco M.A., Partridge L. et al. The hallmarks of aging. Cell 2013;153(6):1194–217. DOI: 10.1016/j.cell.2013.05.039Sanada F., Taniyama Y., Muratsu J. et al. Source of chronic inflammation in aging. Front Cardiovasc Med 2018;5:12. DOI: 10.3389/fcvm.2018.00012Leoni C., Montagner S., Rinaldi A. et al. Dnmt3a restrains mast cell inflammatory responses. Proc Natl Acad Sci USA 2017;114(8):E1490–9. DOI: 10.1073/pnas.1616420114Cull A.H., Snetsinger B., Buckstein R. et al. Tet2 restrains inflammatory gene expression in macrophages. Exp Hematol 2017;55:56–70.e13. DOI: 10.1016/j.exphem.2017.08.001Fabre M.A., de Almeida J.G., Fiorillo E. et al. The longitudinal dynamics and natural history of clonal haematopoiesis. Nature 2022;606(7913):335–42. DOI: 10.1038/s41586­022­04785­zUddin M.M., Saadatagah S., Niroula A. et al. Long­term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis. Nat Commun 2024;15(1):7858. DOI: 10.1038/s41467­024­52302­9Cacic A.M., Schulz F.I., Germing U. et al. Molecular and clinical aspects relevant for counseling individuals with clonal hematopoiesis of indeterminate potential. Front Oncol 2023;13:1303785. DOI: 10.3389/fonc.2023.1303785Kar S.P., Quiros P.M., Gu M. et al. Genome­wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis. Nat Genet 2022;54(8):1155–66. DOI: 10.1038/s41588­022­01121­zLevin M.G., Nakao T., Zekavat S.M. et al. Genetics of smoking and risk of clonal hematopoiesis. Sci Rep 2022;12(1):7248. DOI: 10.1038/s41598­022­09604­zDawoud A.A.Z., Tapper W.J., Cross N.C.P. Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking. Leukemia 2020;34(10):2660–72. DOI: 10.1038/s41375­020­0896­8Kessler M.D., Damask A., O’Keeffe S. et al. Common and rare variant associations with clonal haematopoiesis phenotypes [published correction appears in Nature 2023;615(7950):E3]. Nature 2022;612(7939):301–9. DOI: 10.1038/s41586­022­05448­9Haring B., Reiner A.P., Liu J. et al. Healthy lifestyle and clonal hematopoiesis of indeterminate potential: results from the women’s health initiative. J Am Heart Assoc 2021;10(5):e018789. DOI: 10.1161/JAHA.120.018789Bonnefond A., Skrobek B., Lobbens S. et al. Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nat Genet 2013;45(9):1040–3. DOI: 10.1038/ng.2700Florez M.A., Tran B.T., Wathan T.K. et al. Clonal hematopoiesis: mutation­specific adaptation to environmental change. Cell Stem Cell 2022;29(6):882–904. DOI: 10.1016/j.stem.2022.05.006Joo L., Bradley C.C., Lin S.H. et al. Causes of clonal hematopoiesis : a review. Curr Oncol Rep 2023;25(3):211–20. DOI: 10.1007/s11912­023­01362­zWeber S., Parmon A., Kurrle N. et al. The clinical significance of iron overload and iron metabolism in myelodysplastic syndrome and acute myeloid leukemia. Front Immunol 2021;11:627662. DOI: 10.3389/fimmu.2020.627662Jasra S., Giricz O., Zeig­Owens R. et al. High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster. Nat Med 2022;28(3):468–71. DOI: 10.1038/s41591­022­01708­3Yoshida K., French B., Yoshida N. et al. Radiation exposure and longitudinal changes in peripheral monocytes over 50 years: the Adult Health Study of atomic­bomb survivors. Br J Haematol 2019;185(1):107–15. DOI: 10.1111/bjh.15750Midic D., Rinke J., Perneret F. et al. Prevalence and dynamics of clonal hematopoiesis caused by leukemia­associated mutations in elderly individuals without hematologic disorders. Leukemia 2020;34:2198–205. DOI: 10.1038/s41375­020­0869­yBrojakowska A., Kour A., Thel M.C. et al. Retrospective analysis of somatic mutations and clonal hematopoiesis in astronauts [published correction appears in Commun Biol 2022;5(1):1078]. Commun Biol 2022;5(1):828. DOI: 10.1038/s42003­022­03777­zMencia­Trinchant N., MacKay M.J., Chin C. et al. Clonal hematopoiesis before, during, and after human spaceflight. Cell Rep 2020;33(10):108458. DOI: 10.1016/j.celrep.2020.108458Valent P. ICUS, IDUS, CHIP and CCUS: diagnostic criteria, separation from MDS and clinical implications. Pathobiology 2019;86(1):30–8. DOI: 10.1159/000489042Khoury J.D., Solary E., Abla O. et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 2022;36(7):1703–19. DOI: 10.1038/s41375­022­01613­1Steensma D.P., Ebert B.L. Clonal hematopoiesis as a model for premalignant changes during aging. Exp Hematol 2020;83:48–56. DOI: 10.1016/j.exphem.2019.12.001Gurnari C., Fabiani E., Falconi G. et al. From clonal hematopoiesis to therapy­related myeloid neoplasms: the silent way of cancer progression. Biology (Basel) 2021;10(2):128. DOI: 10.3390/biology10020128Arber D.A., Orazi A., Hasserjian R.P. et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood 2022;140(11):1200–28. DOI: 10.1182/blood.2022015850Bernstein N., Spencer Chapman M., Nyamondo K. et al. Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis. Nat Genet 2024;56(6):1147–55. DOI: 10.1038/s41588­024­01755­1Demajo S., Ramis­Zaldivar J.E., Muiños F. et al. Identification of clonal hematopoiesis driver mutations through in silico saturation mutagenesis. Cancer Discov 2024;14(9):1717–31. DOI: 10.1158/2159­8290.CD­23­1416Ashburner M., Ball C.A., Blake J.A. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000;25(1):25–9. DOI: 10.1038/75556Gene Ontology Consortium. The Gene Ontology resource: enriching a GOld mine. Nucleic Acids Res 2021;49(D1):D325–34. DOI: 10.1093/nar/gkaa1113Kanehisa M., Sato Y. KEGG Mapper for inferring cellular functions from protein sequences. Protein Sci 2020;29(1):28–35. DOI: 10.1002/pro.3711Kanehisa M., Sato Y., Kawashima M. KEGG mapping tools for uncovering hidden features in biological data. Protein Sci 2022;31(1):47–53. DOI: 10.1002/pro.4172Fabregat A., Sidiropoulos K., Viteri G. et al. Reactome diagram viewer: data structures and strategies to boost performance. Bioinformatics 2018;34(7):1208–14. DOI: 10.1093/bioinformatics/btx752Kelder T., Pico A.R., Hanspers K. et al. Mining biological pathways using WikiPathways web services. PLoS One 2009;4(7):e6447. DOI: 10.1371/journal.pone.0006447Agrawal A., Balcı H., Hanspers K. et al. WikiPathways 2024: next generation pathway database. Nucleic Acids Res 2024;52(D1):D679–89. DOI: 10.1093/nar/gkad960Valent P., Orazi A., Steensma D.P. et al. Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre­MDS conditions. Oncotarget 2017;8(43):73483–500. DOI: 10.18632/oncotarget.19008Döhner H., Wei A.H., Appelbaum F.R. et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022;140(12):1345–77. DOI: 10.1182/blood.2022016867Malcovati L., Gallì A., Travaglino E. et al. Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 2017;129:3371–8. DOI: 10.1182/blood­2017­01­763425Garcia­Manero G. Myelodysplastic syndromes: 2023 update on diagnosis, risk­stratification, and management. Am J Hematol 2023;98(8):1307–25. DOI: 10.1002/ajh.26984Niroula A., Sekar A., Murakami M.A. et al. Distinction of lymphoid and myeloid clonal hematopoiesis. Nat Med 2021;27(11):1921–7. DOI: 10.1038/s41591­021­01521­4Dawoud A.A.Z., Gilbert R.D., Tapper W.J., Cross N.C.P. Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease. Leukemia 2022;36(2):507–15. DOI: 10.1038/s41375­021­01382­3Kim P.G., Niroula A., Shkolnik V. et al. Dnmt3a­mutated clonal hematopoiesis promotes osteoporosis. J Exp Med 2021;218(12):e20211872. DOI: 10.1084/jem.20211872Smith C.L., Eppig J.T. The mammalian phenotype ontology: enabling robust annotation and comparative analysis. Wiley Interdiscip Rev Syst Biol Med 2009;1(3):390–9. DOI: 10.1002/wsbm.44Baldarelli R.M., Smith C.L., Ringwald M. et al. Mouse Genome Informatics: an integrated knowledgebase system for the laboratory mouse. Genetics 2024;227(1):iyae031. DOI: 10.1093/genetics/iyae031Piñero J., Queralt­Rosinach N., Bravo À. et al. DisGeNET: a discovery platform for the dynamical exploration of human diseases and their genes. Database (Oxford) 2015;2015:bav028. DOI: 10.1093/database/bav028Valent P., Akin C., Arock M. et al. Proposed terminology and classification of pre­malignant neoplastic conditions: a consensus proposal. EBioMedicine 2017;26:17–24. DOI: 10.1016/j.ebiom.2017.11.024Valent P., Kern W., Hoermann G. et al. Clonal hematopoiesis with oncogenic potential (CHOP): separation from CHIP and roads to AML. Int J Mol Sci 2019;20(3):789. DOI: 10.3390/ijms20030789Cappelli L.V., Meggendorfer M., Baer C. et al. Indeterminate and oncogenic potential: CHIP vs CHOP mutations in AML with NPM1 alteration. Leukemia 2022;36(2):394–402. DOI: 10.1038/s41375­021­01368­1Von Beck K., von Beck T., Ferrell P.B. et al. Lymphoid clonal hematopoiesis: implications for malignancy, immunity, and treatment. Blood Cancer J 2023;13(1):5. DOI: 10.1038/s41408­022­00773­8Valent P., Bain B.J., Bennett J.M. et al. Idiopathic cytopenia of undetermined significance (ICUS) and idiopathic dysplasia of uncertain significance (IDUS), and their distinction from low risk MDS. Leuk Res 2012;36:1–5. DOI: 10.1016/j.leukres.2011.08.016Valent P., Horny H.P., Bennett J.M. et al. Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: consensus statements and report from a working conference. Leuk Res 2007;31:727–36. DOI: 10.1016/j.leukres.2006.11.009Taborda C.C., Zeidan A.M., Mendez L.M. Clonal cytopenia of undetermined significance: definitions, risk and therapeutic targets. Front Hematol 2024;3: 1419323. DOI: 10.3389/frhem.2024.1419323Kern W., Meggendorfer M., Haferlach C., Haferlach T. Integrated diagnostic approach for suspected myelodysplastic syndrome as a basis for advancement of diagnostic criteria. Blood 2016;128(22):299. DOI: 10.1182/blood.V128.22.299.299Mangaonkar A.A., Patnaik M.M. Clonal hematopoiesis of indeterminate potential and clonal cytopenias of undetermined significance: 2023 update on clinical associations and management recommendations. Am J Hematol 2023;98(6):951–64. DOI: 10.1002/ajh.26915Yizhak K., Aguet F., Kim J. et al. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 2019;364(6444):eaaw0726. DOI: 10.1126/science.aaw0726Martincorena I., Fowler J.C., Wabik A. et al. Somatic mutant clones colonize the human esophagus with age. Science 2018;362(6417):911–7. DOI: 10.1126/science.aau3879Keogh M.J., Wei W., Aryaman J. et al. High prevalence of focal and multi­focal somatic genetic variants in the human brain. Nat Commun 2018;9(1):4257. DOI: 10.1038/s41467­018­06331­wDesai P., Mencia­Trinchant N., Savenkov O. et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med 2018;24:1015–23. DOI: 10.1038/s41591­018­0081­zKishtagari A., Khan M.A.W., Li Y. et al. Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk. Blood Cancer J 2024;14(1):6. DOI: 10.1038/s41408­023­00974­9Kleppe M., Comen E., Wen H.Y. et al. Somatic mutations in leukocytes infiltrating primary breast cancers. NPJ Breast Cancer 2015;1:15005. DOI: 10.1038/npjbcancer.2015.5Coombs C.C., Gillis N.K., Tan X. et al. Identification of clonal hematopoiesis mutations in solid tumor patients undergoing unpaired next­generation sequencing assays. Clin Cancer Res 2018;24(23):5918–24. DOI: 10.1158/1078­0432.ccr­18­1201Ptashkin R.N., Mandelker D.L., Coombs C.C. et al. Prevalence of clonal hematopoiesis mutations in tumor­only clinical genomic profiling of solid tumors [published correction appears in JAMA Oncol 2019;5(1):122]. JAMA Oncol 2018;4(11):1589–93. DOI: 10.1001/jamaoncol.2018.2297Marnell C.S., Bick A., Natarajan P. Clonal hematopoiesis of indeterminate potential (CHIP): linking somatic mutations hematopoiesis, chronic inflammation and cardiovascular disease. J Mol Cell Cardiol 2021;161:98–105. DOI: 10.1016/j.yjmcc.2021.07.004