TY - JOUR
T1 - Clonal competition within complex evolutionary hierarchies shapes AML over time
AU - Sandén, Carl
AU - Lilljebjörn, Henrik
AU - Orsmark Pietras, Christina
AU - Henningsson, Rasmus
AU - Saba, Karim H.
AU - Landberg, Niklas
AU - Thorsson, Hanna
AU - von Palffy, Sofia
AU - Peña-Martinez, Pablo
AU - Högberg, Carl
AU - Rissler, Marianne
AU - Gisselsson, David
AU - Lazarevic, Vladimir
AU - Juliusson, Gunnar
AU - Ågerstam, Helena
AU - Fioretos, Thoas
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-019-14106-0
DO - 10.1038/s41467-019-14106-0
M3 - Article
C2 - 32024830
AN - SCOPUS:85079071787
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 579
ER -