A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network
(2016) In Nucleic Acids Research 44(22). p.10644-10661- Abstract
Aberrant stem cell-like gene regulatory networks are a feature of leukaemogenesis. The ETS-related gene (ERG), an important regulator of normal haematopoiesis, is also highly expressed in T-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells. Using this approach, we identified a number of known binders of the +85 enhancer in leukaemic cells along with previously unknown binders, including ETV6 and IKZF1. We confirmed that ETV6 and IKZF1... (More)
Aberrant stem cell-like gene regulatory networks are a feature of leukaemogenesis. The ETS-related gene (ERG), an important regulator of normal haematopoiesis, is also highly expressed in T-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells. Using this approach, we identified a number of known binders of the +85 enhancer in leukaemic cells along with previously unknown binders, including ETV6 and IKZF1. We confirmed that ETV6 and IKZF1 were also bound at the +85 enhancer in both leukaemic cells and in healthy human CD34+ haematopoietic stem and progenitor cells. Knockdown experiments confirmed that ETV6 and IKZF1 are transcriptional regulators not just of ERG, but also of a number of genes regulated by a densely interconnected network of seven transcription factors. At last, we show that ETV6 and IKZF1 expression levels are positively correlated with expression of a number of heptad genes in AML and high expression of all nine genes confers poorer overall prognosis.
(Less)
- author
- organization
- publishing date
- 2016-12-15
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Base Sequence, Binding Sites, Cell Line, Tumor, Consensus Sequence, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, Gene Regulatory Networks, Humans, Ikaros Transcription Factor/physiology, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute/genetics, Prognosis, Proportional Hazards Models, Protein Binding, Proteome, Proteomics, Proto-Oncogene Proteins c-ets/physiology, Repressor Proteins/physiology, Transcription, Genetic, Transcriptional Regulator ERG/physiology
- in
- Nucleic Acids Research
- volume
- 44
- issue
- 22
- pages
- 10644 - 10661
- publisher
- Oxford University Press
- external identifiers
-
- pmid:27604872
- scopus:85009994524
- ISSN
- 1362-4962
- DOI
- 10.1093/nar/gkw804
- language
- English
- LU publication?
- yes
- additional info
- © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.
- id
- 72afdccf-8ed2-422b-a5d0-34b3c146db47
- date added to LUP
- 2020-04-06 16:05:53
- date last changed
- 2024-01-31 19:29:35
@article{72afdccf-8ed2-422b-a5d0-34b3c146db47,
abstract = {{<p>Aberrant stem cell-like gene regulatory networks are a feature of leukaemogenesis. The ETS-related gene (ERG), an important regulator of normal haematopoiesis, is also highly expressed in T-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells. Using this approach, we identified a number of known binders of the +85 enhancer in leukaemic cells along with previously unknown binders, including ETV6 and IKZF1. We confirmed that ETV6 and IKZF1 were also bound at the +85 enhancer in both leukaemic cells and in healthy human CD34+ haematopoietic stem and progenitor cells. Knockdown experiments confirmed that ETV6 and IKZF1 are transcriptional regulators not just of ERG, but also of a number of genes regulated by a densely interconnected network of seven transcription factors. At last, we show that ETV6 and IKZF1 expression levels are positively correlated with expression of a number of heptad genes in AML and high expression of all nine genes confers poorer overall prognosis.</p>}},
author = {{Unnikrishnan, Ashwin and Guan, Yi F and Huang, Yizhou and Beck, Dominik and Thoms, Julie A I and Peirs, Sofie and Knezevic, Kathy and Ma, Shiyong and de Walle, Inge V and de Jong, Ineke and Ali, Zara and Zhong, Ling and Raftery, Mark J and Taghon, Tom and Larsson, Jonas and MacKenzie, Karen L and Van Vlierberghe, Pieter and Wong, Jason W H and Pimanda, John E}},
issn = {{1362-4962}},
keywords = {{Base Sequence; Binding Sites; Cell Line, Tumor; Consensus Sequence; Enhancer Elements, Genetic; Gene Expression Regulation, Leukemic; Gene Regulatory Networks; Humans; Ikaros Transcription Factor/physiology; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute/genetics; Prognosis; Proportional Hazards Models; Protein Binding; Proteome; Proteomics; Proto-Oncogene Proteins c-ets/physiology; Repressor Proteins/physiology; Transcription, Genetic; Transcriptional Regulator ERG/physiology}},
language = {{eng}},
month = {{12}},
number = {{22}},
pages = {{10644--10661}},
publisher = {{Oxford University Press}},
series = {{Nucleic Acids Research}},
title = {{A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network}},
url = {{http://dx.doi.org/10.1093/nar/gkw804}},
doi = {{10.1093/nar/gkw804}},
volume = {{44}},
year = {{2016}},
}