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

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

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Publication Type:: Journal Article
Citation:: Blood, 2013, 121 (12), pp. 2289 - 2300
Issue Date:: 2013-01-01

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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	Basic Helix-Loop-Helix Transcription Factors	en_US
dc.subject.mesh	Enhancer Elements, Genetic	en_US
dc.subject.mesh	LIM Domain Proteins	en_US
dc.subject.mesh	Leukemia, Myeloid, Acute	en_US
dc.subject.mesh	Neoplastic Stem Cells	en_US
dc.subject.mesh	Proto-Oncogene Protein c-fli-1	en_US
dc.subject.mesh	T-Cell Acute Lymphocytic Leukemia Protein 1	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.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 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	12	en_US
pubs.publication-status	Published	en_US
pubs.volume	121	en_US

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/116741