Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia
Diffner, E
Beck, D
Gudgin, E
Thoms, JAI
Knezevic, K
Pridans, C
Foster, S
Goode, D
Lim, WK
Boelen, L
Metzeler, KH
Micklem, G
Bohlander, SK
Buske, C
Burnett, A
Ottersbach, K
Vassiliou, GS
Olivier, J
Wong, JWH
Göttgens, B
Huntly, BJ
Pimanda, JE
- Publication Type:
- Journal Article
- Citation:
- Blood, 2013, 121 (12), pp. 2289 - 2300
- Issue Date:
- 2013-01-01
Closed Access
Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Diffner, E | en_US |
dc.contributor.author | Beck, D | en_US |
dc.contributor.author | Gudgin, E | en_US |
dc.contributor.author | Thoms, JAI | en_US |
dc.contributor.author | Knezevic, K | en_US |
dc.contributor.author | Pridans, C | en_US |
dc.contributor.author | Foster, S | en_US |
dc.contributor.author | Goode, D | en_US |
dc.contributor.author | Lim, WK | en_US |
dc.contributor.author | Boelen, L | en_US |
dc.contributor.author | Metzeler, KH | en_US |
dc.contributor.author | Micklem, G | en_US |
dc.contributor.author | Bohlander, SK | en_US |
dc.contributor.author | Buske, C | en_US |
dc.contributor.author | Burnett, A | en_US |
dc.contributor.author | Ottersbach, K | en_US |
dc.contributor.author | Vassiliou, GS | en_US |
dc.contributor.author | Olivier, J | en_US |
dc.contributor.author | Wong, JWH | en_US |
dc.contributor.author | Göttgens, B | en_US |
dc.contributor.author | Huntly, BJ | en_US |
dc.contributor.author | Pimanda, JE | en_US |
dc.date.issued | 2013-01-01 | en_US |
dc.identifier.citation | Blood, 2013, 121 (12), pp. 2289 - 2300 | en_US |
dc.identifier.issn | 0006-4971 | en_US |
dc.identifier.uri | http://hdl.handle.net/10453/116741 | |
dc.description.abstract | © 2013 by The American Society of Hematology. Aberrant transcriptional programs in combination with abnormal proliferative signaling drive leukemic transformation. These programs operate in normal hematopoiesis where they are involved in hematopoietic stem cell (HSC) proliferation and maintenance. Ets Related Gene (ERG) is a component of normal and leukemic stem cell signatures and high ERG expression is a risk factor for poor prognosis in acute (AML). However, mechanisms that underlie ERG expression in AML and how its expression relates to leukemic stemness are unknown. We report that ERG expression in AML is associated with activity of the ERG promoters and +85 stem cell enhancer and a heptad of transcription factors that combinatorially regulate genes in HSCs. Gene expression signatures derived from ERG promoter–stem cell enhancer and heptad activity are associated with clinical outcome when ERG expression alone fails. We also show that the heptad signature is associated with AMLs that lack somatic mutations in NPM1 and confers an adverse prognosis when associated with FLT3 mutations. Taken together, these results suggest that transcriptional regulators cooperate to establish or maintain primitive stem cell–like signatures in leukemic cells and that the underlying pattern of somatic mutations contributes to the development of these signatures and modulate their influence on clinical outcome. | en_US |
dc.relation.ispartof | Blood | en_US |
dc.relation.isbasedon | 10.1182/blood-2012-07-446120 | en_US |
dc.subject.classification | Immunology | en_US |
dc.subject.mesh | Hematopoietic Stem Cells | en_US |
dc.subject.mesh | Cells, Cultured | en_US |
dc.subject.mesh | K562 Cells | en_US |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Mice, Transgenic | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Mice | en_US |
dc.subject.mesh | Adaptor Proteins, Signal Transducing | en_US |
dc.subject.mesh | Trans-Activators | en_US |
dc.subject.mesh | Neoplasm Proteins | en_US |
dc.subject.mesh | Proto-Oncogene Proteins | en_US |
dc.subject.mesh | Transcription Factors | en_US |
dc.subject.mesh | Prognosis | en_US |
dc.subject.mesh | Gene Expression Regulation, Leukemic | en_US |
dc.subject.mesh | Core Binding Factor Alpha 2 Subunit | en_US |
dc.subject.mesh | GATA2 Transcription Factor | en_US |
dc.subject.mesh | Proto-Oncogene Protein c-fli-1 | en_US |
dc.subject.mesh | Basic Helix-Loop-Helix Transcription Factors | en_US |
dc.subject.mesh | Neoplastic Stem Cells | en_US |
dc.subject.mesh | Leukemia, Myeloid, Acute | en_US |
dc.subject.mesh | Enhancer Elements, Genetic | en_US |
dc.subject.mesh | Transcriptional Activation | en_US |
dc.subject.mesh | LIM Domain Proteins | en_US |
dc.subject.mesh | Transcriptional Regulator ERG | en_US |
dc.subject.mesh | T-Cell Acute Lymphocytic Leukemia Protein 1 | en_US |
dc.subject.mesh | Adaptor Proteins, Signal Transducing | en_US |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Basic Helix-Loop-Helix Transcription Factors | en_US |
dc.subject.mesh | Cells, Cultured | en_US |
dc.subject.mesh | Core Binding Factor Alpha 2 Subunit | en_US |
dc.subject.mesh | Enhancer Elements, Genetic | en_US |
dc.subject.mesh | GATA2 Transcription Factor | en_US |
dc.subject.mesh | Gene Expression Regulation, Leukemic | en_US |
dc.subject.mesh | Hematopoietic Stem Cells | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | K562 Cells | en_US |
dc.subject.mesh | LIM Domain Proteins | en_US |
dc.subject.mesh | Leukemia, Myeloid, Acute | en_US |
dc.subject.mesh | Mice | en_US |
dc.subject.mesh | Mice, Transgenic | en_US |
dc.subject.mesh | Neoplasm Proteins | en_US |
dc.subject.mesh | Neoplastic Stem Cells | en_US |
dc.subject.mesh | Prognosis | en_US |
dc.subject.mesh | Proto-Oncogene Protein c-fli-1 | en_US |
dc.subject.mesh | Proto-Oncogene Proteins | en_US |
dc.subject.mesh | T-Cell Acute Lymphocytic Leukemia Protein 1 | en_US |
dc.subject.mesh | Trans-Activators | en_US |
dc.subject.mesh | Transcription Factors | en_US |
dc.subject.mesh | Transcriptional Activation | en_US |
dc.subject.mesh | Transcriptional Regulator ERG | en_US |
dc.title | Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia | en_US |
dc.type | Journal Article | |
utslib.description.version | Published | en_US |
utslib.citation.volume | 12 | en_US |
utslib.citation.volume | 121 | en_US |
utslib.for | 1103 Clinical Sciences | en_US |
utslib.for | 0903 Biomedical Engineering | en_US |
utslib.for | 1102 Cardiovascular Medicine And Haematology | en_US |
utslib.for | 1103 Clinical Sciences | 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 | 12 | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 121 | en_US |
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Filename | Description | Size | |||
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2289.full.pdf | Published Version | 2.49 MB | Adobe PDF |
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Abstract:
© 2013 by The American Society of Hematology. Aberrant transcriptional programs in combination with abnormal proliferative signaling drive leukemic transformation. These programs operate in normal hematopoiesis where they are involved in hematopoietic stem cell (HSC) proliferation and maintenance. Ets Related Gene (ERG) is a component of normal and leukemic stem cell signatures and high ERG expression is a risk factor for poor prognosis in acute (AML). However, mechanisms that underlie ERG expression in AML and how its expression relates to leukemic stemness are unknown. We report that ERG expression in AML is associated with activity of the ERG promoters and +85 stem cell enhancer and a heptad of transcription factors that combinatorially regulate genes in HSCs. Gene expression signatures derived from ERG promoter–stem cell enhancer and heptad activity are associated with clinical outcome when ERG expression alone fails. We also show that the heptad signature is associated with AMLs that lack somatic mutations in NPM1 and confers an adverse prognosis when associated with FLT3 mutations. Taken together, these results suggest that transcriptional regulators cooperate to establish or maintain primitive stem cell–like signatures in leukemic cells and that the underlying pattern of somatic mutations contributes to the development of these signatures and modulate their influence on clinical outcome.
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