Journal Article

Stem cell gene expression programs influence clinical outcome in human leukemia

van Galen, Peter, Waldron, Levi, Canty, Angelo J, Metzeler, Klaus H, Jurisica, Igor, Nilsson, Björn, Golub, Todd R, Minden, Mark D, Bohlander, Stefan K, Takenaka, Katsuto, Lechman, Eric R, Danska, Jayne S, Ebert, Benjamin L, Buske, Christian, Poeppl, Armando, Beyene, Joseph, Ling, Vicki, Dick, John E, Eppert, Kolja

2011

Overview

By functionally isolating stem cells (LSCs) from individuals with leukemia and parsing our their gene expression, Dick and his colleagues find that LSCs have heterogeneous surface markers and frequencies and possess a gene expression profile resembling that of normal hematopoietic stem cells. The gene expression program derived from LSCs could be a general predictor of disease outcome, stratifying risk for cytogenetically normal patients, which suggests that stemness underlies leukemia aggressiveness. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/191/2018 / 631/67/71 / 692/699/67/1990/283/1897 / Animals / Biomedicine / Cancer Research / Care and treatment / Cellular biology / Clinical outcomes / Colony-Forming Units Assay / Computational Biology / Flow Cytometry / Gene expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Hematopoietic Stem Cells - metabolism / Humans / Infectious Diseases / Leukemia / Leukemia, Myeloid, Acute - metabolism / Leukemia, Myeloid, Acute - physiopathology / Medical prognosis / Metabolic Diseases / Mice / Mice, Inbred NOD / Mice, SCID / Models, Biological / Molecular Medicine / Neoplastic Stem Cells - metabolism / Neurosciences / Patient outcomes / Physiological aspects / Stem cells / Xenograft Model Antitumor Assays