title: Genetic variegation of clonal architecture and propagating cells in leukaemia.
abstract: Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for cancer clone maintenance 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-up to a diagnosis and in relapse. Leukaemia propagating cells, assayed by serial transplantation in NOD/SCID IL2Rγ(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.
authors.affiliation: Section of Haemato-Oncology, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Kristina
authors.initials: K
authors.lastname: Anderson
authors.forename: Christoph
authors.initials: C
authors.lastname: Lutz
authors.forename: Frederik W
authors.initials: FW
authors.lastname: van Delft
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Bateman
authors.forename: Yanping
authors.initials: Y
authors.lastname: Guo
authors.forename: Susan M
authors.initials: SM
authors.lastname: Colman
authors.forename: Helena
authors.initials: H
authors.lastname: Kempski
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.forename: Ian
authors.initials: I
authors.lastname: Titley
authors.forename: John
authors.initials: J
authors.lastname: Swansbury
authors.forename: Lyndal
authors.initials: L
authors.lastname: Kearney
authors.forename: Tariq
authors.initials: T
authors.lastname: Enver
authors.forename: Mel
authors.initials: M
authors.lastname: Greaves
mesh_terms: D000818:Animals; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology*; D050676:Core Binding Factor Alpha 2 Subunit; D056915:DNA Copy Number Variations / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D053631:Interleukin Receptor Common gamma Subunit; D015514:Oncogene Proteins, Fusion; C507942:Il2rg protein, mouse; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein