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Clonal competition within complex evolutionary hierarchies shapes AML over time

Sandén, Carl LU ; Lilljebjörn, Henrik LU ; Orsmark Pietras, Christina LU ; Henningsson, Rasmus LU ; Saba, Karim H. LU ; Landberg, Niklas LU ; Thorsson, Hanna LU ; von Palffy, Sofia LU ; Peña-Martinez, Pablo LU and Högberg, Carl LU , et al. (2020) In Nature Communications 11(1).
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... (More)

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.

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Nature Communications
volume
11
issue
1
article number
579
publisher
Nature Publishing Group
external identifiers
  • pmid:32024830
  • scopus:85079071787
ISSN
2041-1723
DOI
10.1038/s41467-019-14106-0
language
English
LU publication?
yes
id
d0dbcd46-a070-4926-a2d8-41b60ef0871a
date added to LUP
2020-02-14 08:58:33
date last changed
2020-02-26 07:41:44
@article{d0dbcd46-a070-4926-a2d8-41b60ef0871a,
  abstract     = {<p>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.</p>},
  author       = {Sandén, Carl and Lilljebjörn, Henrik and Orsmark Pietras, Christina and Henningsson, Rasmus and Saba, Karim H. and Landberg, Niklas and Thorsson, Hanna and von Palffy, Sofia and Peña-Martinez, Pablo and Högberg, Carl and Rissler, Marianne and Gisselsson, David and Lazarevic, Vladimir and Juliusson, Gunnar and Ågerstam, Helena and Fioretos, Thoas},
  issn         = {2041-1723},
  language     = {eng},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Clonal competition within complex evolutionary hierarchies shapes AML over time},
  url          = {http://dx.doi.org/10.1038/s41467-019-14106-0},
  doi          = {10.1038/s41467-019-14106-0},
  volume       = {11},
  year         = {2020},
}