title: Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity.
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.
authors.affiliation: Division of Cell and Molecular Biology, University Health Network, and Department of Molecular Genetics and Microbiology, University of Toronto, 620 University Avenue, Toronto, Ontario, M5G 2C1, Canada.
authors.forename: Kristin J
authors.initials: KJ
authors.lastname: Hope
authors.forename: Liqing
authors.initials: L
authors.lastname: Jin
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
mesh_terms: D000818:Animals; D002455:Cell Division; D019070:Cell Lineage; D002999:Clone Cells / Q000473:pathology / Q000637:transplantation; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007700:Kinetics; D016086:Lentivirus / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000145:classification* / Q000473:pathology*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured