Single-cell analysis based dissection of clonality in myelofibrosis

Elena Mylonas, Kenichi Yoshida, Mareike Frick, Kaja Hoyer, Friederike Christen, Jaspal Kaeda, Matthias Obenaus, Daniel Noerenberg, Cornelius Hennch, Willy Chan, Yotaro Ochi, Yuichi Shiraishi, Yusuke Shiozawa, Thorsten Zenz, Christopher C. Oakes, Birgit Sawitzki, Michaela Schwarz, Lars Bullinger, Philipp Coutre, Matthew J. J. Rose-Zerilli, Seishi Ogawa and Frederik Damm ()
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Elena Mylonas: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Kenichi Yoshida: Kyoto University
Mareike Frick: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Kaja Hoyer: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Friederike Christen: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Jaspal Kaeda: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Matthias Obenaus: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Daniel Noerenberg: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Cornelius Hennch: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Willy Chan: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Yotaro Ochi: Kyoto University
Yuichi Shiraishi: The University of Tokyo
Yusuke Shiozawa: Kyoto University
Thorsten Zenz: University Hospital Zurich / University of Zurich
Christopher C. Oakes: The Ohio State University
Birgit Sawitzki: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Medical Immunology
Michaela Schwarz: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Lars Bullinger: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Philipp Coutre: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology
Matthew J. J. Rose-Zerilli: University of Southampton
Seishi Ogawa: Kyoto University
Frederik Damm: Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hematology, Oncology, and Tumor Immunology

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Cancer development is an evolutionary genomic process with parallels to Darwinian selection. It requires acquisition of multiple somatic mutations that collectively cause a malignant phenotype and continuous clonal evolution is often linked to tumor progression. Here, we show the clonal evolution structure in 15 myelofibrosis (MF) patients while receiving treatment with JAK inhibitors (mean follow-up 3.9 years). Whole-exome sequencing at multiple time points reveal acquisition of somatic mutations and copy number aberrations over time. While JAK inhibition therapy does not seem to create a clear evolutionary bottleneck, we observe a more complex clonal architecture over time, and appearance of unrelated clones. Disease progression associates with increased genetic heterogeneity and gain of RAS/RTK pathway mutations. Clonal diversity results in clone-specific expansion within different myeloid cell lineages. Single-cell genotyping of circulating CD34 + progenitor cells allows the reconstruction of MF phylogeny demonstrating loss of heterozygosity and parallel evolution as recurrent events.

Date: 2020
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DOI: 10.1038/s41467-019-13892-x

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