Clonal competition within complex evolutionary hierarchies shapes AML over time

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 and Thoas Fioretos ()
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Carl Sandén: Lund University
Henrik Lilljebjörn: Lund University
Christina Orsmark Pietras: Lund University
Rasmus Henningsson: Lund University
Karim H. Saba: Lund University
Niklas Landberg: Lund University
Hanna Thorsson: Lund University
Sofia von Palffy: Lund University
Pablo Peña-Martinez: Lund University
Carl Högberg: Lund University
Marianne Rissler: Lund University
David Gisselsson: Lund University
Vladimir Lazarevic: Skåne University Hospital
Gunnar Juliusson: Skåne University Hospital
Helena Ågerstam: Lund University
Thoas Fioretos: Lund University

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-14106-0

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