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Multiple myeloma, gammopathies

Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis

Leukemia volume 32, pages 1908–1919 (2018)Cite this article

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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 Lin−CD34+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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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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Author notes

  1. These authors contributed equally: Christopher Maximilian Arends, Joel Galan-Sousa, and Kaja Hoyer.

  2. Mareike Frick and Frederik Damm jointly supervised this work.

Authors and Affiliations

  1. Department of Hematology, Oncology, and Tumor Immunology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

    Christopher Maximilian Arends, Joel Galan-Sousa, Kaja Hoyer, Willy Chan, Daniel Noerenberg, Nils Waldhueter, Helga Fleischer-Notter, Friederike Christen, Clemens A. Schmitt, Bernd Dörken, Uwe Pelzer, Marianne Sinn, Annegret Kunitz, Lars Bullinger, Elena Mylonas, Mareike Frick & Frederik Damm

  2. Berlin Institute of Health (BIH) Core Genomics Facility, Charité, University Medical Center, Berlin, Germany

    Marten Jäger, Tomasz Zemojtel & Ulrike Krüger

  3. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kenichi Yoshida & Seishi Ogawa

  4. Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Centre for Musculoskeletal Surgery, Berlin, Germany

    Ricarda Seemann & Sven Märdian

  5. Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine in the Helmholtz Association; Nephrology and Intensive Care Medicine, Berlin, Germany

    Adrian Schreiber

  6. German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

    Frederik Damm

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  1. Christopher Maximilian Arends
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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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