Article

Evolution of human BCR—ABL1 lymphoblastic leukaemia-initiating cells

Division of Stem Cell and Developmental Biology, Campbell Family Institute for Cancer Research/Ontario Cancer Institute, Toronto, Ontario M5G 1L7, Canada.
Nature (Impact Factor: 42.35). 03/2011; 471(7337):254. DOI: 10.1038/nature09877
Source: PubMed

ABSTRACT Many tumours are composed of genetically diverse cells; however, little
is known about how diversity evolves or the impact that diversity has on
functional properties. Here, using xenografting and DNA copy number
alteration (CNA) profiling of human BCR-ABL1 lymphoblastic leukaemia, we
demonstrate that genetic diversity occurs in functionally defined
leukaemia-initiating cells and that many diagnostic patient samples
contain multiple genetically distinct leukaemia-initiating cell
subclones. Reconstructing the subclonal genetic ancestry of several
samples by CNA profiling demonstrated a branching multi-clonal evolution
model of leukaemogenesis, rather than linear succession. For some
patient samples, the predominant diagnostic clone repopulated
xenografts, whereas in others it was outcompeted by minor subclones.
Reconstitution with the predominant diagnosis clone was associated with
more aggressive growth properties in xenografts, deletion of CDKN2A and
CDKN2B, and a trend towards poorer patient outcome. Our findings link
clonal diversity with leukaemia-initiating-cell function and underscore
the importance of developing therapies that eradicate all intratumoral
subclones.

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