Stem cell gene expression programs influence clinical outcome in human leukemia

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

doi:10.1038/nm.2415

Stem cell gene expression programs influence clinical outcome in human leukemia

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

Center for Cellular and Molecular Medicine

Research output: Contribution to journal › Article › peer-review

730 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1086-1094
Number of pages	9
Journal	Nature medicine
Volume	17
Issue number	9
DOIs	https://doi.org/10.1038/nm.2415
Publication status	Published - Sept 2011

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm.2415

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Eppert, K., Takenaka, K., Lechman, E. R., Waldron, L., Nilsson, B., Van Galen, P., Metzeler, K. H., Poeppl, A., Ling, V., Beyene, J., Canty, A. J., Danska, J. S., Bohlander, S. K., Buske, C., Minden, M. D., Golub, T. R., Jurisica, I., Ebert, B. L., & Dick, J. E. (2011). Stem cell gene expression programs influence clinical outcome in human leukemia. Nature medicine, 17(9), 1086-1094. https://doi.org/10.1038/nm.2415

Eppert, K, Takenaka, K, Lechman, ER, Waldron, L, Nilsson, B, Van Galen, P, Metzeler, KH, Poeppl, A, Ling, V, Beyene, J, Canty, AJ, Danska, JS, Bohlander, SK, Buske, C, Minden, MD, Golub, TR, Jurisica, I, Ebert, BL & Dick, JE 2011, 'Stem cell gene expression programs influence clinical outcome in human leukemia', Nature medicine, vol. 17, no. 9, pp. 1086-1094. https://doi.org/10.1038/nm.2415

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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.",

author = "Kolja Eppert and Katsuto Takenaka and Lechman, {Eric R.} and Levi Waldron and Bj{\"o}rn Nilsson and {Van Galen}, Peter and Metzeler, {Klaus H.} and Armando Poeppl and Vicki Ling and Joseph Beyene and Canty, {Angelo J.} and Danska, {Jayne S.} and Bohlander, {Stefan K.} and Christian Buske and Minden, {Mark D.} and Golub, {Todd R.} and Igor Jurisica and Ebert, {Benjamin L.} and Dick, {John E.}",

note = "Funding Information: This work was in part supported by grants from the German Ministry of Education and Research (BMBF; C.B. and S.K.B., 01GS0448 and 01GS0876); the Deutsche Forschungsgemeinschaft (C.B., BU-1177/3-1); Ontario Research Fund (I.J., GL2-01-030); a fellowship (K.E.) and grants (J.E.D.) from the Leukemia and Lymphoma Society; the Stem Cell Network of Canadian National Centres of Excellence (J.E.D.); the Canadian Cancer Society Research Institute (J.E.D.); Ministry of Education, Culture, Sports, Science and Technology in Japan (20591134, K.T.); the Terry Fox Foundation (J.E.D.); Genome Canada through the Ontario Genomics Institute (J.E.D.); Ontario Institute for Cancer Research with funds from the province of Ontario (J.E.D.); the Canadian Institutes for Health Research (J.E.D.); and a Canada Research Chair (J.E.D. and I.J.). Computational resources were supported in part by Canada Foundation for Innovation (12301 and 203383) and IBM (I.J.). 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 OMOHLTC.",

year = "2011",

month = sep,

doi = "10.1038/nm.2415",

language = "English",

volume = "17",

pages = "1086--1094",

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T1 - Stem cell gene expression programs influence clinical outcome in human leukemia

AU - Eppert, Kolja

AU - Takenaka, Katsuto

AU - Lechman, Eric R.

AU - Waldron, Levi

AU - Nilsson, Björn

AU - Van Galen, Peter

AU - Metzeler, Klaus H.

AU - Poeppl, Armando

AU - Ling, Vicki

AU - Beyene, Joseph

AU - Canty, Angelo J.

AU - Danska, Jayne S.

AU - Bohlander, Stefan K.

AU - Buske, Christian

AU - Minden, Mark D.

AU - Golub, Todd R.

AU - Jurisica, Igor

AU - Ebert, Benjamin L.

AU - Dick, John E.

N1 - Funding Information: This work was in part supported by grants from the German Ministry of Education and Research (BMBF; C.B. and S.K.B., 01GS0448 and 01GS0876); the Deutsche Forschungsgemeinschaft (C.B., BU-1177/3-1); Ontario Research Fund (I.J., GL2-01-030); a fellowship (K.E.) and grants (J.E.D.) from the Leukemia and Lymphoma Society; the Stem Cell Network of Canadian National Centres of Excellence (J.E.D.); the Canadian Cancer Society Research Institute (J.E.D.); Ministry of Education, Culture, Sports, Science and Technology in Japan (20591134, K.T.); the Terry Fox Foundation (J.E.D.); Genome Canada through the Ontario Genomics Institute (J.E.D.); Ontario Institute for Cancer Research with funds from the province of Ontario (J.E.D.); the Canadian Institutes for Health Research (J.E.D.); and a Canada Research Chair (J.E.D. and I.J.). Computational resources were supported in part by Canada Foundation for Innovation (12301 and 203383) and IBM (I.J.). 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 OMOHLTC.

PY - 2011/9

Y1 - 2011/9

N2 - 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.

AB - 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.

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JO - Nature Medicine

JF - Nature Medicine

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ER -

Stem cell gene expression programs influence clinical outcome in human leukemia

Abstract

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