Abstract
Emerging evidence suggests cancer stem cells sustain neoplasms; however, little is understood of the normal cell initially targeted and the resultant cancer stem cells. We show here, by tracking individual human leukemia stem cells (LSCs) in nonobese diabetic–severe combined immunodeficiency mice serially transplanted with acute myeloid leukemia cells, that LSCs are not functionally homogeneous but, like the normal hematopoietic stem cell (HSC) compartment, comprise distinct hierarchically arranged LSC classes. Distinct LSC fates derived from heterogeneous self-renewal potential. Some LSCs emerged only in recipients of serial transplantation, indicating they divided rarely and underwent self-renewal rather than commitment after cell division within primary recipients. Heterogeneity in LSC self-renewal potential supports the hypothesis that they derive from normal HSCs. Furthermore, normal developmental processes are not completely abolished during leukemogenesis. The existence of multiple stem cell classes shows the need for LSC-targeted therapies.
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Acknowledgements
We thank M. Minden (Princess Margaret Hospital, Toronto, Ontario, Canada) and E. Warren (Hutchinson Cancer Center, Seattle, Washington, USA) for providing AML samples; and members of the Dick lab, M. Minden, N. Iscove and C. Jordan for critical comments on the manuscript. Supported by the Leukemia Research Fund of Canada (L.J.) and Canadian Institutes for Health Research (L.J. and K.H.); and The Stem Cell Network of the National Centres of Excellence, National Cancer Institute of Canada and Canadian Cancer Society, Canadian Genetic Diseases Network of the National Centres of Excellence, Canadian Institutes for Health Research, and Canada Research (J.E.D.).
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Hope, K., Jin, L. & Dick, J. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 5, 738–743 (2004). https://doi.org/10.1038/ni1080
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DOI: https://doi.org/10.1038/ni1080
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