title: Stem cell gene expression programs influence clinical outcome in human leukemia.
abstract: Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying 'stemness' properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.
authors.affiliation: Division of Stem Cell and Developmental Biology, Campbell Family Institute for Cancer Research, Ontario Cancer Institute, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kolja
authors.initials: K
authors.lastname: Eppert
authors.forename: Katsuto
authors.initials: K
authors.lastname: Takenaka
authors.forename: Eric R
authors.initials: ER
authors.lastname: Lechman
authors.forename: Levi
authors.initials: L
authors.lastname: Waldron
authors.forename: Björn
authors.initials: B
authors.lastname: Nilsson
authors.forename: Peter
authors.initials: P
authors.lastname: van Galen
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.forename: Armando
authors.initials: A
authors.lastname: Poeppl
authors.forename: Vicki
authors.initials: V
authors.lastname: Ling
authors.forename: Joseph
authors.initials: J
authors.lastname: Beyene
authors.forename: Angelo J
authors.initials: AJ
authors.lastname: Canty
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Danska
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.forename: Christian
authors.initials: C
authors.lastname: Buske
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
mesh_terms: D000818:Animals; D003114:Colony-Forming Units Assay; D019295:Computational Biology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays