Clonal competition within complex evolutionary hierarchies shapes AML over time

Research output: Contribution to journalArticle

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.

Details

Authors
Organisations
External organisations
  • Skåne University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Cancer and Oncology
Original languageEnglish
Article number579
JournalNature Communications
Volume11
Issue number1
Publication statusPublished - 2020
Publication categoryResearch
Peer-reviewedYes