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Thoas Fioretos

Thoas Fioretos

Research team manager

Thoas Fioretos

Clonal competition within complex evolutionary hierarchies shapes AML over time

Author

  • Carl Sandén
  • Henrik Lilljebjörn
  • Christina Orsmark Pietras
  • Rasmus Henningsson
  • Karim H. Saba
  • Niklas Landberg
  • Hanna Thorsson
  • Sofia von Palffy
  • Pablo Peña-Martinez
  • Carl Högberg
  • Marianne Rissler
  • David Gisselsson
  • Vladimir Lazarevic
  • Gunnar Juliusson
  • Helena Ågerstam
  • Thoas Fioretos
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Summary, in English

Clonal heterogeneity and evolution has major implications for disease progression and relapse in acute myeloid leukemia (AML). To model clonal dynamics in vivo, we serially transplanted 23 AML cases to immunodeficient mice and followed clonal composition for up to 15 months by whole-exome sequencing of 84 xenografts across two generations. We demonstrate vast changes in clonality that both progress and reverse over time, and define five patterns of clonal dynamics: Monoclonal, Stable, Loss, Expansion and Burst. We also show that subclonal expansion in vivo correlates with a more adverse prognosis. Furthermore, clonal expansion enabled detection of very rare clones with AML driver mutations that were undetectable by sequencing at diagnosis, demonstrating that the vast majority of AML cases harbor multiple clones already at diagnosis. Finally, the rise and fall of related clones enabled deconstruction of the complex evolutionary hierarchies of the clones that compete to shape AML over time.

Department/s

  • LUCC: Lund University Cancer Centre
  • Translational Genomic and Functional Studies of Leukemia
  • Genetic chaos in aggressive cancer
  • Targeted therapies in leukemia
  • Division of Clinical Genetics
  • Pathways of cancer cell evolution
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy

Publishing year

2020

Language

English

Publication/Series

Nature Communications

Volume

11

Issue

1

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Medical Genetics
  • Cancer and Oncology

Status

Published

Research group

  • Translational Genomic and Functional Studies of Leukemia
  • Genetic chaos in aggressive cancer
  • Targeted therapies in leukemia
  • Pathways of cancer cell evolution

ISBN/ISSN/Other

  • ISSN: 2041-1723