期刊
NATURE
卷 469, 期 7330, 页码 362-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature09733
关键词
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资金
- Canadian Institutes for Health Research (CIHR)
- Pew Charitable Trusts
- Stem Cell Network of Canadian National Centres of Excellence
- Canadian Cancer Society
- Terry Fox Foundation, Genome Canada through the Ontario Genomics Institute
- Ontario Institute for Cancer Research
- province of Ontario
- Leukemia and Lymphoma Society
- Canadian Institutes for Health Research
- Canada Research Chair
- American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital
- Ontario Ministry of Health and Long Term Care (OMOHLTC)
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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