Clonal hematopoiesis of indeterminate potential and malignant neoplasms

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with aging and is a risk factor of many diseases including malignant neoplasms (MNPs). It originates through somatic mutations in hematopoietic stem and/or progenitor cells, promotes development of hematological MNPs and underlies unfavorable prognosis in solid malignant tumors. Results of recent largescale genome-wide studies confirmed that CHIP plays a role in oncological diseases. Mutations associated with this pathology were found in stem and/or progenitor cells in patients with both hematological and solitary MNPs which indicates that CHIP potentially mediates development of malignant tumors. Cytotoxic chemoradiation therapy is closely associated with CHIP development and causes emergence of aggressive and treatment-resistant hematological MNPs. In patients with solitary MNPs, TET2 gene mutations with high variant allele frequencies were also found in the tumors. This phenomenon was named tumor-infiltrating clonal hemopoiesis. Further populational studies of patients with solitary MNPs will allow to evaluate the role of tumor-infiltrating clonal hemopoiesis in oncogenesis. The ability of age-associated somatic clonal expansions in one tissue, namely hematopoietic compartment, to affect oncogenesis in another tissue is a new concept requiring further investigation and potentially capable of providing deeper understanding of cancer biology.
The review explores the association between CHIP, aging, and oncological diseases with a particular emphasis on solitary MNPs. The ways for better understanding of the role of CHIP in oncogenesis and possibilities of using its clinical potential for cancer treatment are discussed.

1. Verovskaya E.V., Dellorusso P.V., Passegué E. Losing sense of self and surroundings: hematopoietic stem cell aging and leukemic transformation. Trends Mol Med 2019;25(6):494–515. DOI: 10.1016/j.molmed.2019.04.006

2. Genovese G., Kähler A.K., Handsaker R.E. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014;371(26):2477–87. DOI: 10.1056/NEJMoa1409405

3. Jaiswal S., Fontanillas P., Flannick J. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014;371(26):2488–98. DOI: 10.1056/NEJMoa1408617

4. Evans M.A., Walsh K. Clonal hematopoiesis, somatic mosaicism, and age-associated disease. Physiol Rev 2023;103:649–716. DOI: 10.1152/physrev.00004.2022

5. Lee-Six H., Øbro N.F., Shepherd M.S. et al. Population dynamics of normal human blood inferred from somatic mutations. Nature 2018;561(7724):473–8. DOI: 10.1038/s41586-018-0497-0

6. Mitchell E., Chapman M.S, Williams N. et al. Clonal dynamics of haematopoiesis across the human lifespan. Nature 2022;606(7913):343–50. DOI: 10.1038/s41586-022-04786-y

7. Welch 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.2012.06.023

8. Steensma 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/blood-2015-03-631747

9. Steensma D.P. Clinical implications of clonal hematopoiesis. Mayo Clin Proc 2018;93(8):1122–30. DOI: 10.1016/j.mayocp.2018.04.002

10. Coombs C.C., Zehir A., Devlin S.M. et al. Therapy-related clonal hematopoiesis in patients with non hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 2017;21(3):374–82.e4. DOI: 10.1016/j.stem.2017.07.010

11. Kashlakova A.I., Biderman B.V., Parovichnikova E.N. Clonal hematopoiesis and acute myeloid leukemias. Onkogematologiya = Oncogematology 2023;18(3):92–101. (In Russ.). DOI: 10.17650/1818-8346-2023-18-3-92-101

12. Tan H.S.V., Jiang H., Wang S.S.Y. Biomarkers in clonal haematopoiesis of indeterminate potential (CHIP) linking cardiovascular diseases, myeloid neoplasms and inflammation. Ann Hematol 2025;104(3):1355–66. DOI: 10.1007/s00277-025-06244-x

13. Heuser M., Thol F., Ganser A. Clonal hematopoiesis of indeterminate potential. Dtsch Arztebl Int 2016;113(18):317–22. DOI: 10.3238/arztebl.2016.0317

14. Bick A.G., Nandakumar S.K., Fulco C.P. et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 2020;586(7831):763–8. DOI: 10.1038/s41586-020-2819

15. Loh P.R., Genovese G., Handsaker R.E. et al. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Nature 2018;559(7714):350–5. DOI: 10.1038/s41586-018-0321-x

16. Loh P.R., Genovese G., McCarroll S.A. Monogenic and polygenic inheritance become instruments for clonal selection. Nature 2020;584(7819):136–141. DOI: 10.1038/s41586-020-2430-6

17. Niroula 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/s41591-021-01521-4

18. Fulop T., Witkowski J.M., Olivieri F. et al. The integration of inflammaging in age related diseases. Semin Immunol 2018;40:17–35. DOI: 10.1016/j.smim.2018.09.003

19. Bryukhovetsky A.S., Bryukhovetsky I.S. The postgenomic theory of human aging and the scientific justification for the use of lowmanipulated biomedical cellular preparations of autologous bone marrow for anti-aging, increasing human life expectancy and longevity. Nauchnyj obozrevatel’ = Scientific Observer 2020;8(116):33–57. (In Russ.).

20. Ktena Y.P., Koldobskiy M.A., Barbato M.I. et al. Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation. J Clin Invest 2022;132(13):e158047. DOI: 10.1172/JCI158047

21. Jakobsen N.A., Turkalj S., Zeng A.G.X. et al. Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging. Cell Stem Cell 2024;31(8):1127–44.e1117. DOI: 10.1016/j.stem.2024.05.010

22. Winter S., Gotze K.S., Hecker J.S. et al. Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche. Leukemia 2024;38(5): 936–46. DOI: 10.1038/s41375-024-02226-6

23. SanMiguel J.M., Young K., Trowbridge J.J. Hand in hand: intrinsic and extrinsic drivers of aging and clonal hematopoiesis. Exp Hematol 2020;91:1–9. DOI: 10.1016/j.exphem.2020.09.197

24. Fabre 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/s41586-022-04785-z

25. Van Zeventer I.A., de Graaf A.O., Salzbrunn J.B. et al. Evolutionary landscape of clonal hematopoiesis in 3,359 individuals from the general population. Cancer Cell 2023;41(6):1017–31.e4. DOI: 10.1016/j.ccell.2023.04.006

26. Jaiswal S., Ebert B.L. Clonal hematopoiesis in human aging and disease. Science 2019;366(6465):eaan4673. DOI: 10.1126/science.aan4673

27. Jakubek Y.A., Reiner A.P., Honigberg M.C. Risk Factors for clonal hematopoiesis of indeterminate potential and mosaic chromosomal alterations. Transl Res 2023;255:171–80. DOI: 10.1016/j.trsl.2022.11.009

28. Kusne Y., Xie Z., Patnaik M.M. Clonal hematopoiesis: Molecular and clinical implications. Leuk Res 2022;113:106787. DOI: 10.1016/j.leukres.2022.106787

29. Petinati N.A., Drize N.I. Clonal hematopoiesis and its role in the development of hematological diseases. Gematologiya i transfuziologiya = Hematology and Transfusiology 2021;66(4): 580–92. (In Russ.). DOI: 10.35754/0234-5730-2021-66-4-580-592

30. Jaiswal S., Natarajan P., Silver A. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. New Engl J Med 2017;377(2):111–21. DOI: 10.1056/ nejmoa1701719

31. Gondek L.P. CHIP: is clonal hematopoiesis a surrogate for aging and other disease? Hematol Amer Soc Hematol Educ Program 2021;2021(1):384–9. DOI: 10.1182/hematology.2021000270

32. Goldman E.A., Spellman P.T., Agarwal A. Defining clonal hematopoiesis of indeterminate potential: evolutionary dynamics and detection under aging and inflammation. Cold Spring Harb Mol Case Stud 2023;9(2):a006251. DOI: 10.1101/mcs.a006251

33. Greaves M., Maley C.C. Clonal evolution in cancer. Nature 2012;481(7381):306–13. DOI: 10.1038/nature10762

34. Takeshima H., Ushijima T. Accumulation of genetic and epigenetic alterations in normal cells and cancer risk. NPJ Precis Oncol 2019;3:7. DOI: 10.1038/s41698-019-0079-0

35. Florez M.A., Tran B.T., Wathan T.K. et al. Clonal hematopoiesis: Mutation-specific adaptation to environmental change. Cell Stem Cell 2022;29(6):882–904. DOI: 10.1016/j.stem.2022.05.006

36. Busque L., Mio R., Mattioli J. et al. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 1996;88(1):59–65.

37. Quiros P.M., Vassiliou G.S. Genetic predisposition to clonal hematopoiesis. Hemasphere 2023;7(9):e947. DOI: 10.1097/HS9.0000000000000947

38. Vijg J., Dong X. Pathogenic mechanisms of somatic mutation and genome mosaicism in aging. Cell 2020;182(1):12–23. DOI: 10.1016/j.cell.2020.06.024

39. Joo 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/s11912-023-01362-z

40. McKerrell T., Park N., Moreno T. et al. Leukemia associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep 2015;10(8):1239–45. DOI: 10.1016/j.celrep.2015.02.005

41. Kessler M.D., Damask A., O’Keeffe S. et al. Common and rare variant associations with clonal haematopoiesis phenotypes. Nature 2022;612(7939):301–9. DOI: 10.1038/s41586-022-05448-9

42. Travaglini S., Marinoni M., Visconte V. et al. Therapy-related myeloid neoplasm: Biology and mechanistic aspects of malignant progression. Biomedicines 2024;12(5):1054. DOI: 10.3390/biomedicines12051054

43. Desai P., Mencia-Trinchant N., Savenkov O. et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med 2018;24(7):1015–23. DOI: 10.1038/s41591-018-0081

44. Abelson S., Collord G., Weissbrod O. et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 2018;559(7714):400–4. DOI: 10.1038/s41586-018-0317-6

45. Kishtagari 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/s41408-023-00974-9

46. Bowman R.L., Busque L., Levine R.L. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 2018;22(2):157–70. DOI: 10.1016/j.stem.2018.01.011

47. Kar S.P., Quiros P.M., Gu M. et al. Genome-wide 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/s41588-022-01121-z

48. Von Beck K., von Beck T., Ferrell Jr.P.B. et al. Lymphoid clonal hematopoiesis: Implications for malignancy, immunity, and treatment. Blood Cancer J 2023;13(1):5. DOI: 10.1038/s41408 -022-00773-8

49. Buttigieg M.M., Rauh M.J. Clonal hematopoiesis: Updates and implications at the solid tumor-immune interface. JCO Precis Oncol 2023;7:e2300132. DOI: 10.1200/PO.23.00132

50. Bolton K.L., Ptashkin R.N., Gao T. et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat Genet 2020;52(11):1219–26. DOI: 10.1038/s41588-020-00710-0

51. Pich O., Reyes-Salazar I., Gonzalez-Perez A. et al. Discovering the drivers of clonal hematopoiesis. Nat Commun 2022;13(1):4267. DOI: 10.1038/s41467-022-31878-0

52. Nguyen Y.T.M, Fujisawa M., Ishikawa S. et al. Clonal hematopoiesis and solid cancers. Cancer Sci 2025;116(8):2055–63. DOI: 10.1111/cas.70097

53. Yun J.K., Kim S., An H. et al. Pre-operative clonal hematopoiesis is related to adverse outcome in lung cancer after adjuvant therapy. Genome Med 2023;15(10):111. DOI: 10.1186/s13073-023-01266-4

54. Levin 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/s41598-022-09604-z

55. Hosoya N., Miyagawa K. Implications of the germline variants of DNA damage response genes detected by cancer precision medicine for radiological risk communication and cancer therapy decisions. J Radiat Res 2021;62(1):i44–52. DOI: 10.1093/jrr/rrab009

56. Tian R., Wiley B., Liu J. et al. Clonal hematopoiesis and risk of incident lung cancer. J Clin Oncol 2023;41(7):1423–33. DOI: 10.1200/JCO.22.00857

57. Zhang Y., Yao Y., Xu Y. et al. Pan-cancer circulating tumor DNA detection in over 10,000 Chinese patients. Nat Commun 2021;12(1):11. DOI: 10.1038/s41467-020-20162-8

58. Diplas B.H., Ptashkin R., Chou J.F. et al. Clinical importance of clonal hematopoiesis in metastatic gastrointestinal tract cancers. JAMA Netw Open 2023;6(2):e2254221. DOI: 10.1001/jamanetworkopen.2022.54221

59. Xu E., Su K., Zhou Y. et al. Comprehensive landscape and interference of clonal haematopoiesis mutations for liquid biopsy: a Chinese pan-cancer cohort. J Cell Mol Med 2021;25(21):10279–90. DOI: 10.1111/ jcmm. 16966

60. Hong W., Li A., Liu Y. et al. Clonal hematopoiesis mutations in patients with lung cancer are associated with lung cancer risk factors. Cancer Res 2022;82(2):199–209. DOI: 10.1158/0008-5472.CAN-21-1903

61. Weber-Lassalle K., Ernst C., Reuss A. et al. Clonal hematopoiesis–associated gene mutations in a clinical cohort of 448 patients with ovarian cancer. J Natl Cancer Inst 2021;114(4):565–70. DOI: 10.1093/jnci/djab231

62. Boucai L., Ptashkin R.N., Levine R.L. et al. Effects of radioactive iodine on clonal hematopoiesis in patients with thyroid cancer: a prospective study. Clin Endocrinol 2023;99(1):122–9. DOI: 10.1111/cen.14925

63. Tiedje V., Vela P.S., Yang J.L. et al. Targetable treatment resistance in thyroid cancer with clonal hematopoiesis. bioRxiv 2024:2024.10.10.617685. DOI: 10.1101/2024.10.10.617685

64. Baranwal A., Hahn C.N., Shah M.V. et al. Role of germline predisposition to therapy-related myeloid neoplasms. Curr Hematol Malig Rep 2022;17(6):254–65. DOI: 10.1007/s11899-022-00676-2

65. Wong T.N., Ramsingh G., Young A.L. et al. The role of TP53 mutations in the origin and evolution of therapy-related AML. Nature 2014;518(7540):552–5. DOI: 10.1038/nature13968

66. Voso M.T., Falconi G., Fabiani E. What’s new in the pathogenesis and treatment of therapy-related myeloid neoplasms. Blood 2021;138(9):749–57. DOI: 10.1182/blood.2021010764

67. Franco S., Godley L.A. Genetic and environmental risks for clonal hematopoiesis and cancer. J Exp Med 2025;6;222(1):e20230931. DOI: 10.1084/jem.20230931

68. Swanton C., Bernard E., Abbosh C. et al. Embracing cancer complexity: Hallmarks of systemic disease. Cell 2024;187(7): 1589–616. DOI: 10.1016/j.cell.2024.02.009

69. Park M.D., Le Berichel J., Hamon P. et al. Hematopoietic aging promotes cancer by fueling IL-1α-driven emergency myelopoiesis. Science 2024;386(6720):eadn0327. DOI: 10.1126/science.adn0327

70. Pich O., Bernard E., Zagorulya M. et al. Tumor-infiltrating clonal hematopoiesis. N Engl J Med 2025;392(16):1594–608. DOI: 10.1056/NEJMoa2413361

71. Ptashkin R.N., Mandelker D.L., Coombs C.C. et al. Prevalence of clonal hematopoiesis mutations in tumor-only clinical genomic profiling of solid tumors. JAMA Oncol 2018;4(11):1589–93. DOI: 10.1001/jamaoncol.2018.2297

72. Kleppe 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.2015.5

73. Coombs C.C., Gillis N.K., Tan X. et al. Identification of clonal hematopoiesis mutations in solid tumor patients undergoing unpaired next-generation sequencing assays. Clin Cancer Res 2018;24(23):5918–24. DOI: 10.1158/1078-0432.ccr-18-1201