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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We would like to thank S. Minkin for statistical analysis of patient outcome, the Dick Laboratory and B. Neel for critical review of this manuscript, M. Cooper for editorial assistance, and P. A. Penttilä, L. Jamieson, J. Yuan and S. Zhao for preparative flow cytometry. This work was supported by funds from Canadian Institutes for Health Research (CIHR) studentships (F.N., S.D.), the Pew Charitable Trusts (C.G.M.), The Stem Cell Network of Canadian National Centres of Excellence, the Canadian Cancer Society and the Terry Fox Foundation, Genome Canada through the Ontario Genomics Institute, Ontario Institute for Cancer Research with funds from the province of Ontario, the Leukemia and Lymphoma Society, the Canadian Institutes for Health Research, a Canada Research Chair, and the American and Lebanese Syrian Associated Charities of St Jude Children’s Research Hospital. This research was funded in part by the Ontario Ministry of Health and Long Term Care (OMOHLTC). The views expressed do not necessarily reflect those of the OMOHLTC.
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A rare subgroup of leukemia stem cells harbors relapse-inducing potential in acute lymphoblastic leukemia
Experimental Hematology (2019)