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Multiple myeloma, gammopathies

Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) occurs in an age-related manner and associates with an increased risk of hematologic cancer, atherosclerotic disease, and shorter overall survival. Little is known about the cell of origin, repartition patterns of clonal mutations within the hematopoietic differentiation tree, and its dynamics under evolutionary pressure. Using targeted sequencing, CHIP was identified in 121 out of 437 elderly individuals (27.7%). Variant allele frequencies (VAFs) of 91 mutations were studied in six peripheral blood cell fractions. VAFs were significantly higher in monocytes, granulocytes, and NK-cells compared to B- or T cells. In all cases with available bone marrow material, mutations could be identified in LinCD34+CD38 HSCs with subsequent expansion to myeloid primed progenitors. In 22 patients with solid cancer receiving (radio-)chemotherapy, longitudinal study of 32 mutations at 121 time points identified relative VAF changes of at least 50% in 13/32 mutations. VAFs of DNMT3A, were stable in 12/13 cases (P < .001). Cancer patients with a clonal mutation other than DNMT3A required more often red blood cell transfusions and dose reductions. Our results provide novel insights into cellular distribution of clonal mutations, their dynamics under chemotherapy, and advocate for systematic analyses for CHIP in cancer patients.

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References

  1. 1.

    Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. 2.

    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. New Engl J Med. 2014;371:2488–98.

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. New Engl J Med. 2014;371:2477–87.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012;44:1179–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. 5.

    Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373:35–47.

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506:328–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. 7.

    Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR, et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med. 2012;4:149ra118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. 8.

    Damm F, Mylonas E, Cosson A, Yoshida K, Della Valle V, Mouly E, et al. Acquired initiating mutations in early hematopoietic cells of CLL patients. Cancer Discov. 2014;4:1088–101.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Woll PS, Kjallquist U, Chowdhury O, Doolittle H, Wedge DC, Thongjuea S, et al. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell. 2014;25:794–808.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Levine RL, Belisle C, Wadleigh M, Zahrieh D, Lee S, Chagnon P, et al. X-inactivation-based clonality analysis and quantitative JAK2V617F assessment reveal a strong association between clonality and JAK2V617F in PV but not ET/MMM, and identifies a subset of JAK2V617F-negative ET and MMM patients with clonal hematopoiesis. Blood. 2006;107:4139–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. 11.

    Schmidt M, Rinke J, Schafer V, Schnittger S, Kohlmann A, Obstfelder E, et al. Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status. Leukemia. 2014;28:2292–9.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Quivoron C, Couronne L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell. 2011;20:25–38.

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Couronne L, Bastard C, Bernard OA. TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med. 2012;366:95–6.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. 15.

    Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. New Engl J Med. 2017;377:111–21.

    Article  PubMed  Google Scholar 

  16. 16.

    Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355:842–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. 17.

    Gibson CJ, Lindsley RC, Tchekmedyian V, Mar BG, Shi J, Jaiswal S, et al. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J Clin Oncol. 2017;35:1598–605. Jco2016716712

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. 18.

    Takahashi K, Wang F, Kantarjian H, Doss D, Khanna K, Thompson E, et al. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 2017;18:100–11.

    Article  PubMed  Google Scholar 

  19. 19.

    Gillis NK, Ball M, Zhang Q, Ma Z, Zhao Y, Yoder SJ, et al. Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol. 2017;18:112–21.

    Article  PubMed  Google Scholar 

  20. 20.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. 21.

    Damm F, Chesnais V, Nagata Y, Yoshida K, Scourzic L, Okuno Y, et al. BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders. Blood. 2013;122:3169–77.

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Young E, Noerenberg D, Mansouri L, Ljungstrom V, Frick M, Sutton LA, et al. EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia. Leukemia. 2017;31:1547–54.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Mansouri L, Noerenberg D, Young E, Mylonas E, Abdulla M, Frick M, et al. Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma. Blood. 2016;128:2666–70.

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. q-bioGN 2013.

  25. 25.

    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 26.

    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25:2078–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 27.

    Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L, et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012;22:568–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 28.

    Jager M, Wang K, Bauer S, Smedley D, Krawitz P, Robinson PN. Jannovar: a java library for exome annotation. Human Mutat. 2014;35:548–55.

    Article  Google Scholar 

  29. 29.

    Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. 30.

    Thorvaldsdottir H, Robinson JT, Mesirov JP. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 2013;14:178–92.

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Garrison EGM. Haplotype-based variant detection from short-read sequencing. arXiv preprint arXiv:12073907[q-bioGN] 2012.

  32. 32.

    Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9.

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Damm F, Kosmider O, Gelsi-Boyer V, Renneville A, Carbuccia N, Hidalgo-Curtis C, et al. Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood. 2012;119:3211–8.

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Kon A, Shih LY, Minamino M, Sanada M, Shiraishi Y, Nagata Y, et al. Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat Genet. 2013;45:1232–7.

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Thol F, Bollin R, Gehlhaar M, Walter C, Dugas M, Suchanek KJ, et al. Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications. Blood. 2014;123:914–20.

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150:264–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 37.

    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Moretta L, Bottino C, Pende D, Mingari MC, Biassoni R, Moretta A. Human natural killer cells: their origin, receptors and function. Eur J Immunol. 2002;32:1205–11.

    Article  PubMed  CAS  Google Scholar 

  39. 39.

    Buscarlet M, Provost S, Feroz Zada Y, Barhdadi A, Bourgoin V, Lepine G, et al. DNMT3A and TET2 dominate clonal hematopoiesis, demonstrate benign phenotypes and different genetic predisposition. Blood. 2017;130:753–62.

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Coombs CC, Zehir A, Devlin SM, Kishtagari A, Syed A, Jonsson P, et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell. 2017;21:374–82. e4

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. 41.

    Malcovati L, Galli A, Travaglino E, Ambaglio I, Rizzo E, Molteni E, et al. Clinical significance of somatic mutation in unexplained blood cytopenia. Blood. 2017;129:3371–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  42. 42.

    Guryanova OA, Shank K, Spitzer B, Luciani L, Koche RP, Garrett-Bakelman FE, et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med. 2016;22:1488–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Wong TN, Miller CA, Klco JM, Petti A, Demeter R, Helton NM, et al. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood. 2016;127:893–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. 44.

    Palomero T, Couronne L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014;46:166–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. 45.

    Thol F, Klesse S, Kohler L, Gabdoulline R, Kloos A, Liebich A, et al. Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis. Leukemia. 2017;31:1286–95.

    Article  PubMed  CAS  Google Scholar 

  46. 46.

    Pei W, Feyerabend TB, Rossler J, Wang X, Postrach D, Busch K, et al. Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. Nature. 2017;548:456–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. 47.

    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Article  PubMed  Google Scholar 

  48. 48.

    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. 49.

    Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, Horsman D, et al. Circos: an information aesthetic for comparative genomics. Genome Res. 2009;19:1639–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This study was supported by grants #DA1787/1–1 from the Deutsche Forschungsgemeinschaft, #2015_A09 and #2017_EKES.33 from the Else Kröner-Fresenius-Stiftung, a Mechthild-Harf fellowship from the DKMS, and the Lady Tata Memorial Trust awarded to F.D.; C.M.A. received a fellowship from the Berlin Institute of Health (BIH), J.G.-S. received funding fellowship from the Berliner Krebsgesellschaft, and W.C. received a fellowship from the Deutsche José Carreras Leukämie-Stiftung. D.N., M.F., and F.D. are fellows of the Charité Clinician Scientist Program funded by the Charité University Medical Center Berlin and the BIH. The authors would like to thank Eva Beerbaum and Kathleen Hunt for technical assistance, Axel Pruß for help collecting transfusion data, and Danuta Ochab for assisting cytology. We would like to acknowledge the assistance of the BCRT Flow Cytometry Lab.

Author contributions

F.D. designed the research; C.M.A., J.G.-S., K.H., W.C., M.J., K.Y., R.S., D.N., N.W., H.F.-N., F.C., C.A.S., B.D., U.P., M.S., T.Z., S.O., S.M., A.S., A.K., U.K., L.B., E.M., M.F., and F.D. performed the research and/or contributed patient samples and clinical data; C.M.A., J.G.-S., K.H., M.J., K.Y., E.M., M.F., and F.D. analyzed the data; C.M.A, J.G.-S., M.F. and F.D. wrote the paper. All authors read and agreed to the final version of the manuscript.

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Correspondence to Frederik Damm.

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Arends, C.M., Galan-Sousa, J., Hoyer, K. et al. Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis. Leukemia 32, 1908–1919 (2018). https://doi.org/10.1038/s41375-018-0047-7

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