Stem cell gene expression programs influence clinical outcome in human leukemia

被引：804

作者：

Eppert, Kolja ^{[1
,2
]}

Takenaka, Katsuto ^{[3
]}

Lechman, Eric R. ^{[1
,2
]}

Waldron, Levi ^{[4
]}

Nilsson, Bjoern ^{[5
]}

van Galen, Peter ^{[1
,2
]}

Metzeler, Klaus H. ^{[6
]}

Poeppl, Armando ^{[1
,2
]}

Ling, Vicki ^{[7
]}

Beyene, Joseph ^{[7
]}

Canty, Angelo J. ^{[8
]}

Danska, Jayne S. ^{[4
,9
,10
]}

Bohlander, Stefan K. ^{[6
]}

Buske, Christian ^{[11
]}

Minden, Mark D. ^{[12
]}

Golub, Todd R. ^{[13
]}

Jurisica, Igor ^{[4
]}

Ebert, Benjamin L. ^{[5
]}

Dick, John E. ^{[1
,2
]}

机构：

[1] Univ Toronto, Ontario Canc Inst, Div Stem Cell & Dev Biol, Campbell Family Inst Canc Res,Univ Hlth Network, Toronto, ON, Canada

[2] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[3] Kyushu Univ, Dept Med & Biosyst Sci, Grad Sch Med Sci, Fukuoka 812, Japan

[4] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[5] Brigham & Womens Hosp, Boston, MA 02115 USA

[6] Univ Munich, Dept Internal Med 2, Munich, Germany

[7] Hosp Sick Children, Res Inst, Toronto, ON M5G 1X8, Canada

[8] McMaster Univ, Dept Math & Stat, Hamilton, ON, Canada

[9] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada

[10] Univ Toronto, Dept Immunol, Toronto, ON, Canada

[11] Univ Hosp Ulm, Inst Expt Canc Res, Ctr Comprehens Canc, Ulm, Germany

[12] Univ Hlth Network, Dept Med, Toronto, ON, Canada

[13] Broad Inst, Cambridge, MA USA

来源：

NATURE MEDICINE | 2011年 / 17卷 / 09期

基金：

加拿大创新基金会;

关键词：

ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; INTRAFEMORAL TRANSPLANTATION; CANCER; AML; MUTATIONS; SIGNATURE; RARE; HETEROGENEITY; ASSOCIATION;

D O I：

10.1038/nm.2415

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1086 / U91

页数：9

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