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Bedeutung der klonalen Hämatopoese für hämatologische Neoplasien

Importance of clonal hematopoiesis for hematologic neoplasms

  • Schwerpunkt: Klonale Hämatopoese
  • Published:
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Zusammenfassung

Hintergrund

Die klonale Hämatopoese von unbestimmtem Potenzial (CHIP) ist ein relativ neu beschriebenes Phänomen, bei dem mit myeloischen Neoplasien assoziierte somatische Mutationen im peripheren Blut von Personen ohne Anzeichen einer hämatologischen Erkrankung nachweisbar sind. Personen mit CHIP haben ein deutlich erhöhtes Risiko, eine hämatologische Neoplasie zu entwickeln, obwohl die Gesamtrate der Transformation gering ist.

Fragestellung

Wir geben hier einen Überblick über den aktuellen Wissensstand zu den Ursachen der klonalen Expansion von Blutzellen sowie zu den identifizierbaren Risikofaktoren für die Entwicklung einer hämatologischen Neoplasie.

Ergebnisse und Schlussfolgerung

Die CHIP gilt als prämaligner Zustand und prädisponiert für die Entwicklung einer hämatologischen Neoplasie. Da die Transformationsrate insgesamt niedrig ist, ist die eindeutige Identifizierung und anschließende Überwachung von CHIP-Patienten mit höherem Risiko von größter Bedeutung. In Zukunft könnten prospektive Studien zur Bewertung präventiver therapeutischer Strategien helfen, die Entwicklung von Blutkrebs bei Personen mit CHIP zu verhindern.

Abstract

Background

Clonal hematopoiesis of indeterminate potential (CHIP) is a fairly newly described phenomenon characterized by myeloid cancer-associated somatic mutations detectable in the peripheral blood of individuals without evidence of hematologic disease. Individuals with CHIP have a significantly increased risk of developing a hematologic malignancy, although the overall rate of transformation is low.

Objective

We review the current state of knowledge on causes of clonal expansion of blood cells as well as identifiable risk factors for progression to overt hematologic malignancy.

Results and conclusion

CHIP is considered a premalignant state and predisposes to the development of hematologic malignancy. Because the overall rate of transformation is low, clear identification and subsequent monitoring of those CHIP individuals at a higher risk is of paramount importance. In the future, prospective studies evaluating preventive and/or preemptive therapeutic strategies may aid in avoiding progression to blood cancer in individuals with CHIP.

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Literatur

  1. Jaiswal S, Fontanillas P, Flannick J et al (2014) Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371:2488–2498

    Article  PubMed  PubMed Central  Google Scholar 

  2. Genovese G, Jaiswal S, Ebert BL, McCarroll SA (2015) Clonal hematopoiesis and blood-cancer risk. N Engl J Med 372:1071–1072

    Article  CAS  PubMed  Google Scholar 

  3. Xie M, Lu C, Wang J et al (2014) Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20:1472–1478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Young AL, Challen GA, Birmann BM, Druley TE (2016) Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun 7:12484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Steensma DP, Bejar R, Jaiswal S et al (2015) Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126:9–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zink F, Stacey SN, Norddahl GL et al (2017) Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130:742–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hecker JS, Hartmann L, Rivière J et al (2021) CHIP and hips: clonal hematopoiesis is common in patients undergoing hip arthroplasty and is associated with autoimmune disease. Blood 138:1727–1732

    Article  CAS  PubMed  Google Scholar 

  8. Bowman RL, Busque L, Levine RL (2018) Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 22:157–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Khoury JD, Solary E, Abla O et al (2022) The 5th edition of the world health organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. https://doi.org/10.1038/s41375-022-01613-1

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fuster JJ, Zuriaga MA, Zorita V et al (2020) TET2-loss-of-function-driven clonal hematopoiesis exacerbates experimental insulin resistance in aging and obesity. Cell Rep 33:108326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Agrawal M, Niroula A, Cunin P et al (2021) The association between clonal hematopoiesis and gout. Blood 138:595–595

    Article  Google Scholar 

  12. Kim PG, Niroula A, Shkolnik V et al (2021) Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis. J Exp Med. https://doi.org/10.1084/jem.20211872

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jaiswal S, Natarajan P, Silver AJ et al (2017) Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 377:111–121

    Article  PubMed  PubMed Central  Google Scholar 

  14. Niroula A, Sekar A, Murakami MA et al (2021) Distinction of lymphoid and myeloid clonal hematopoiesis. Nat Med 27:1921–1927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jaiswal S, Ebert BL (2019) Clonal hematopoiesis in human aging and disease. Science. https://doi.org/10.1126/science.aan4673

    Article  PubMed  PubMed Central  Google Scholar 

  16. Mitchell E, Spencer Chapman M, Williams N et al (2022) Clonal dynamics of haematopoiesis across the human lifespan. Nature 606:343–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fabre MA, de Almeida JG, Fiorillo E et al (2022) The longitudinal dynamics and natural history of clonal haematopoiesis. Nature 606:335–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Challen GA, Goodell MA (2020) Clonal hematopoiesis: mechanisms driving dominance of stem cell clones. Blood 136:1590–1598

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Florez MA, Tran BT, Wathan TK, DeGregori J, Pietras EM, King KY (2022) Clonal hematopoiesis: mutation-specific adaptation to environmental change. Cell Stem Cell 29:882–904

    Article  CAS  PubMed  Google Scholar 

  20. van den Akker EB, Pitts SJ, Deelen J et al (2016) Uncompromised 10-year survival of oldest old carrying somatic mutations in DNMT3A and TET2. Blood 127:1512–1515

    Article  PubMed  PubMed Central  Google Scholar 

  21. Buscarlet M, Provost S, Zada YF et al (2017) DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130:753–762

    Article  CAS  PubMed  Google Scholar 

  22. Hinds DA, Barnholt KE, Mesa RA et al (2016) Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood 128:1121–1128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Janiszewska H, Bąk A, Skonieczka K et al (2018) Constitutional mutations of the CHEK2 gene are a risk factor for MDS, but not for de novo AML. Leuk Res 70:74–78

    Article  CAS  PubMed  Google Scholar 

  24. Kennedy AL, Myers KC, Bowman J et al (2021) Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome. Nat Commun 12:1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fuster JJ, MacLauchlan S, Zuriaga MA et al (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355:842–847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Abegunde SO, Buckstein R, Wells RA, Rauh MJ (2018) An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp Hematol 59:60–65

    Article  CAS  PubMed  Google Scholar 

  27. Avagyan S, Henninger JE, Mannherz WP et al (2021) Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis. Science 374:768–772

    Article  CAS  PubMed  Google Scholar 

  28. Weeks LD, Marinac CR, Redd R et al (2022) Age-related diseases of inflammation in myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 139:1246–1250

    Article  CAS  PubMed  Google Scholar 

  29. Chen J, Nie D, Wang X et al (2021) Enriched clonal hematopoiesis in seniors with dietary vitamin C inadequacy. Clin Nutr ESPEN 46:179–184

    Article  PubMed  Google Scholar 

  30. Meisel M, Hinterleitner R, Pacis A et al (2018) Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557:580–584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zeng H, He H, Guo L et al (2019) Antibiotic treatment ameliorates ten-eleven translocation 2 (TET2) loss-of-function associated hematological malignancies. Cancer Lett 467:1–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rodriguez-Meira A, Norfo R, Wen WX et al (2022) Deciphering TP53 mutant cancer evolution with single-cell multi-omics (bioRxiv)

    Book  Google Scholar 

  33. Kar SP, Quiros PM, Gu M et al (2022) Genome-wide analyses of 200,453 individuals yields new insights into the causes and consequences of clonal hematopoiesis https://doi.org/10.1101/2022.01.06.22268846 (bioRxiv)

    Book  Google Scholar 

  34. SanMiguel JM, Eudy E, Loberg MA et al (2022) Distinct tumor necrosis factor alpha receptors dictate stem cell fitness versus lineage output in Dnmt3a-mutant clonal hematopoiesis (bioRxiv)

    Google Scholar 

  35. Coombs CC, Zehir A, Devlin SM et al (2017) Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21:374–382.e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gillis NK, Ball M, Zhang Q et al (2017) Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol 18:112–121

    Article  PubMed  Google Scholar 

  37. Hsu JI, Dayaram T, Tovy A et al (2018) PPM1D mutations drive clonal Hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell 23:700–713.e6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dawoud AAZ, Tapper WJ, Cross NCP (2020) Clonal myelopoiesis in the UK biobank cohort: ASXL1 mutations are strongly associated with smoking. Leukemia 34:2660–2672

    Article  CAS  PubMed  Google Scholar 

  39. Wong TN, Ramsingh G, Young AL et al (2015) Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 518:552–555

    Article  CAS  PubMed  Google Scholar 

  40. Lindsley RC, Saber W, Mar BG et al (2017) Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med 376:536–547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zajkowicz A, Butkiewicz D, Drosik A, Giglok M, Suwiński R, Rusin M (2015) Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients. Br J Cancer 112:1114–1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Swisher EM, Harrell MI, Norquist BM et al (2016) Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. JAMA Oncol 2:370–372

    Article  PubMed  PubMed Central  Google Scholar 

  43. Bolton KL, Ptashkin RN, Gao T et al (2020) Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat Genet 52:1219–1226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yoshizato T, Dumitriu B, Hosokawa K et al (2015) Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med 373:35–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kulasekararaj AG, Jiang J, Smith AE et al (2014) Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome. Blood 124:2698–2704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang CRC, Nix D, Gregory M et al (2019) Inflammatory cytokines promote clonal hematopoiesis with specific mutations in ulcerative colitis patients. Exp Hematol 80:36–41.e3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Savola P, Lundgren S, Keränen MAI et al (2018) Clonal hematopoiesis in patients with rheumatoid arthritis. Blood Cancer J. https://doi.org/10.1038/s41408-018-0107-2

    Article  PubMed  PubMed Central  Google Scholar 

  48. Arends CM, Weiss M, Christen F et al (2020) Clonal hematopoiesis in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Haematologica 105:e264–7

    Article  PubMed  PubMed Central  Google Scholar 

  49. Ertz-Archambault N, Kosiorek H, Taylor GE et al (2017) Association of therapy for autoimmune disease with myelodysplastic syndromes and acute myeloid leukemia. JAMA Oncol 3:936–943

    Article  PubMed  PubMed Central  Google Scholar 

  50. van Zeventer IA, de Graaf AO, Wouters HJCM et al (2020) Mutational spectrum and dynamics of clonal hematopoiesis in anemia of older individuals. Blood 135:1161–1170

    PubMed  Google Scholar 

  51. Malcovati L, Gallì A, Travaglino E et al (2017) Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 129:3371–3378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rossi M, Meggendorfer M, Zampini M et al (2021) Clinical relevance of clonal hematopoiesis in persons aged ≥80 years. Blood 138:2093–2105

    Article  CAS  PubMed  Google Scholar 

  53. Abelson S, Collord G, Ng SWK et al (2018) Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 107:2099

    Google Scholar 

  54. Desai P, Mencia-Trinchant N, Savenkov O et al (2018) Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med 24:1–12

    Article  Google Scholar 

  55. Steensma DP, Bolton KL (2020) What to tell your patient with clonal hematopoiesis and why: insights from 2 specialized clinics. Blood 136:1623–1631

    PubMed  PubMed Central  Google Scholar 

  56. Ridker PM, Everett BM, Thuren T et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131

    Article  CAS  PubMed  Google Scholar 

  57. Svensson EC, Madar A, Campbell CD et al (2022) TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol 7:521–528

    Article  PubMed  Google Scholar 

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Correspondence to Katharina S. Götze.

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K.S. Götze und C. Lengerke geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autorinnen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Michael Hallek, Köln

Claudia Lengerke, Tübingen

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Götze, K., Lengerke, C. Bedeutung der klonalen Hämatopoese für hämatologische Neoplasien. Innere Medizin 63, 1107–1114 (2022). https://doi.org/10.1007/s00108-022-01401-0

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