MLL-AF9 Expression in Hematopoietic Stem Cells Drives a Highly Invasive AML Expressing EMT-Related Genes Linked to Poor Outcome

被引：184

作者：

Stavropoulou, Vaia ^{[1
]}

Kaspar, Susanne ^{[2
,3
]}

Brault, Laurent ^{[1
]}

Sanders, Mathijs A. ^{[4
]}

Juge, Sabine ^{[1
]}

Morettini, Stefano ^{[2
]}

Tzankov, Alexandar ^{[5
]}

Iacovino, Michelina ^{[6
]}

Lau, I-Jun ^{[7
]}

Milne, Thomas A. ^{[7
]}

Royo, Helene

Kyba, Michael ^{[8
]}

Valk, Peter J. M.

Peters, Antoine H. F. M. ^{[2
,3
]}

Schwaller, Juerg ^{[1
]}

机构：

[1] Univ Basel, Univ Childrens Hosp UKBB, Dept Biomedicine, CH-4031 Basel, Switzerland

[2] Friedrich Miescher Inst Biomed Res FMI, Maulbeerstr 66, CH-4058 Basel, Switzerland

[3] Univ Basel, Fac Sci, CH-4031 Basel, Switzerland

[4] Erasmus Univ, Med Ctr, Dept Hematol, NL-3015 CE Rotterdam, Netherlands

[5] Univ Basel Hosp, Inst Pathol, CH-4031 Basel, Switzerland

[6] LA Biomed Res Inst, Dept Pediat, Torrance, CA 90502 USA

[7] Univ Oxford, Weatherall Inst Mol Med, MRC Mol Haematol Unit, NIHR Oxford Biomed Res Ctr Programme, Oxford OX3 9DS, England

[8] Univ Minnesota, Dept Pediat, Lillehei Heart Inst, Minneapolis, MN 55455 USA

来源：

CANCER CELL | 2016年 / 30卷 / 01期

基金：

英国医学研究理事会; 瑞士国家科学基金会;

关键词：

CANCER-CELLS; PROMOTES; TRANSFORMATION; PATHOGENESIS; MAINTENANCE; PLASTICITY; SUBSET; ORIGIN; EVI1; ERG;

D O I：

10.1016/j.ccell.2016.05.011

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

To address the impact of cellular origin on acute myeloid leukemia (AML), we generated an inducible transgenic mouse model for MLL-AF9-driven leukemia. MLL-AF9 expression in long-term hematopoietic stem cells (LT-HSC) in vitro resulted in dispersed clonogenic growth and expression of genes involved in migration and invasion. In vivo, 20% LT-HSC-derived AML were particularly aggressive with extensive tissue infiltration, chemoresistance, and expressed genes related to epithelial-mesenchymal transition (EMT) in solid cancers. Knockdown of the EMT regulator ZEB1 significantly reduced leukemic blast invasion. By classifying mouse and human leukemias according to Evi1/EVI1 and Erg/ERG expression, reflecting aggressiveness and cell of origin, and performing comparative transcriptomics, we identified several EMT-related genes that were significantly associated with poor overall survival of AML patients.

引用

页码：43 / 58

页数：16

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