Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia

被引：44

作者：

Goldberg, Liat ^{[1
,2
]}

Tijssen, Marloes R. ^{[3
,4
,5
]}

Birger, Yehudit ^{[1
]}

Hannah, Rebecca L. ^{[3
,4
,5
]}

Kinston, Sarah J. ^{[3
,4
,5
]}

Schuette, Judith ^{[3
,4
,5
]}

Beck, Dominik ^{[6
,7
]}

Knezeyic, Kathy ^{[6
,7
]}

Schiby, Ginette ^{[8
,9
]}

Jacob-Hirsch, Jasmine ^{[1
]}

Biran, Anat ^{[10
]}

Kloog, Yoel ^{[10
]}

Marcucci, Guido ^{[11
]}

Bloomfield, Clara D. ^{[11
]}

Aplan, Peter D. ^{[12
]}

Pimanda, John E. ^{[6
,7
]}

Goettgens, Berthold ^{[3
,4
,5
]}

Izraeli, Shai ^{[1
,2
]}

机构：

[1] Chaim Sheba Med Ctr, Canc Res Ctr, IL-52621 Ramat Gan, Israel

[2] Tel Aviv Univ, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel

[3] Univ Cambridge, Dept Hematol, Cambridge Inst Med Res, Cambridge, England

[4] Univ Cambridge, Wellcome Trust, Cambridge, England

[5] Univ Cambridge, MRC, Cambridge Stem Cell Inst, Cambridge, England

[6] Univ New S Wales, Lowy Canc Res Ctr, Sydney, NSW, Australia

[7] Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia

[8] Chaim Sheba Med Ctr, Dept Pathol, Tel Aviv, Israel

[9] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel

[10] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel

[11] Ohio State Univ, Ctr Comprehens Canc, Div Hematol & Oncol, Dept Internal Med, Columbus, OH 43210 USA

[12] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

来源：

BLOOD | 2013年 / 122卷 / 15期

基金：

英国生物技术与生命科学研究理事会; 以色列科学基金会; 英国惠康基金;

关键词：

PIM SERINE/THREONINE KINASES; ACUTE LYMPHOBLASTIC-LEUKEMIA; REGULATORY CIRCUIT; CELLS; GENE; INHIBITOR; CANCER; ETS; IDENTIFICATION; MEGAKARYOCYTE;

D O I：

10.1182/blood-2013-01-477133

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The ETS transcription factor ERG plays a central role in definitive hematopoiesis, and its overexpression in acute myeloid leukemia (AML) is associated with a stem cell signature and poor prognosis. Yet how ERG causes leukemia is unclear. Here we show that pan-hematopoietic ERG expression induces an early progenitor myeloid leukemia in transgenic mice. Integrated genome-scale analysis of gene expression and ERG binding profiles revealed that ERG activates a transcriptional program similar to human AML stem/progenitor cells and to human AML with high ERG expression. This transcriptional program was associated with activation of RAS that was required for leukemia cells growth in vitro and in vivo. We further show that ERG induces expression of the Pim1 kinase oncogene through a novel hematopoietic enhancer validated in transgenic mice and human CD34(+) normal and leukemic cells. Pim1 inhibition disrupts growth and induces apoptosis of ERG-expressing leukemic cells. The importance of the ERG/PIM1 axis is further underscored by the poorer prognosis of AML highly expressing ERG and PIM1. Thus, integrative genomic analysis demonstrates that ERG causes myeloid progenitor leukemia characterized by an induction of leukemia stem cell transcriptional programs. Pim1 and the RAS pathway are potential therapeutic targets of these high-risk leukemias.

引用

页码：2694 / 2703

页数：10

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