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Genetic variegation of clonal architecture and propagating cells in leukaemia

Lookup NU author(s): Dr Frederik van DelftORCiD, Professor Anthony MoormanORCiD

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Abstract

Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for cancer clonemaintenance and propagation. Here we have examined this issue in childhood acute lymphoblastic leukaemia in which the ETV6-RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or 'driver' copy number alterations. By multiplexing fluorescence in situ hybridization probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of subclones identified and a composite picture of subclonal architecture and putative ancestral trees assembled. Subclones in acute lymphoblastic leukaemia have variegated genetics and complex, nonlinear or branching evolutionary histories. Copy number alterations are independently and reiteratively acquired in subclones of individual patients, and in no preferential order. Clonal architecture is dynamic and is subject to change in the lead-upto a diagnosis and in relapse. Leukaemia propagating cells, assayed by serial transplantation in NOD/SCID IL2R gamma(null) mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive regenerative capacity in vivo. These data have implications for cancer genomics and for the targeted therapy of cancer.

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Author(s): Anderson K, Lutz C, van Delft FW, Bateman CM, Guo YP, Colman SM, Kempski H, Moorman AV, Titley I, Swansbury J, Kearney L, Enver T, Greaves M

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2011

Volume: 469

Issue: 7330

Pages: 356-361

Print publication date: 15/12/2010

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nature09650

DOI: 10.1038/nature09650

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