Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia
Goldberg, L
Tijssen, MR
Birger, Y
Hannah, RL
Kinston, SJ
Schütte, J
Beck, D
Knezevic, K
Schiby, G
Jacob-Hirsch, J
Biran, A
Kloog, Y
Marcucci, G
Bloomfield, CD
Aplan, PD
Pimanda, JE
Göttgens, B
Izraeli, S
- Publication Type:
- Journal Article
- Citation:
- Blood, 2013, 122 (15), pp. 2694 - 2703
- Issue Date:
- 2013-10-10
Closed Access
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2694.full.pdf | Published Version | 2.01 MB | Adobe PDF |
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Goldberg, L | en_US |
dc.contributor.author | Tijssen, MR | en_US |
dc.contributor.author | Birger, Y | en_US |
dc.contributor.author | Hannah, RL | en_US |
dc.contributor.author | Kinston, SJ | en_US |
dc.contributor.author | Schütte, J | en_US |
dc.contributor.author | Beck, D | en_US |
dc.contributor.author | Knezevic, K | en_US |
dc.contributor.author | Schiby, G | en_US |
dc.contributor.author | Jacob-Hirsch, J | en_US |
dc.contributor.author | Biran, A | en_US |
dc.contributor.author | Kloog, Y | en_US |
dc.contributor.author | Marcucci, G | en_US |
dc.contributor.author | Bloomfield, CD | en_US |
dc.contributor.author | Aplan, PD | en_US |
dc.contributor.author | Pimanda, JE | en_US |
dc.contributor.author | Göttgens, B | en_US |
dc.contributor.author | Izraeli, S | en_US |
dc.date.issued | 2013-10-10 | en_US |
dc.identifier.citation | Blood, 2013, 122 (15), pp. 2694 - 2703 | en_US |
dc.identifier.issn | 0006-4971 | en_US |
dc.identifier.uri | http://hdl.handle.net/10453/116739 | |
dc.description.abstract | 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 panhematopoietic ERG expression induces a nearly progenitor myeloid leukemia in trans genic 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. © 2013 by The American Society of Hematology. | en_US |
dc.relation.ispartof | Blood | en_US |
dc.relation.isbasedon | 10.1182/blood-2013-01-477133 | en_US |
dc.subject.classification | Immunology | en_US |
dc.subject.mesh | Myeloid Progenitor Cells | en_US |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Mice, Inbred NOD | en_US |
dc.subject.mesh | Mice, Transgenic | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Mice | en_US |
dc.subject.mesh | Mice, SCID | en_US |
dc.subject.mesh | Trans-Activators | en_US |
dc.subject.mesh | Transcription Factors | en_US |
dc.subject.mesh | Antineoplastic Agents | en_US |
dc.subject.mesh | Neoplasm Transplantation | en_US |
dc.subject.mesh | Genomics | en_US |
dc.subject.mesh | Transcription, Genetic | en_US |
dc.subject.mesh | Gene Expression Regulation, Leukemic | en_US |
dc.subject.mesh | Proto-Oncogene Proteins c-pim-1 | en_US |
dc.subject.mesh | Leukemia, Myeloid, Acute | en_US |
dc.subject.mesh | Enhancer Elements, Genetic | en_US |
dc.subject.mesh | Transcriptional Regulator ERG | en_US |
dc.title | Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia | en_US |
dc.type | Journal Article | |
utslib.citation.volume | 15 | en_US |
utslib.citation.volume | 122 | en_US |
utslib.for | 1103 Clinical Sciences | en_US |
utslib.for | 0903 Biomedical Engineering | en_US |
utslib.for | 1102 Cardiorespiratory Medicine and Haematology | en_US |
utslib.for | 1114 Paediatrics and Reproductive Medicine | en_US |
pubs.embargo.period | Not known | en_US |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology/School of Software | |
pubs.organisational-group | /University of Technology Sydney/Strength - AAI - Advanced Analytics Institute Research Centre | |
pubs.organisational-group | /University of Technology Sydney/Strength - CHT - Health Technologies | |
utslib.copyright.status | closed_access | |
pubs.issue | 15 | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 122 | en_US |
Abstract:
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 panhematopoietic ERG expression induces a nearly progenitor myeloid leukemia in trans genic 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. © 2013 by The American Society of Hematology.
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