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A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network

(2016) NUCLEIC ACIDS RESEARCH. 44(22). p.10644-10661
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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 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.
Keywords
ACUTE LYMPHOBLASTIC-LEUKEMIA, ACUTE MYELOID-LEUKEMIA, FACTOR-BINDING PROFILES, GENOME-WIDE ANALYSIS, STEM-CELL, DEFINITIVE HEMATOPOIESIS, HISTONE METHYLATION, MASS-SPECTROMETRY, HIGH EXPRESSION, GATA FACTORS

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Chicago
Unnikrishnan, Ashwin, Yi Fang Guan, Yizhou Huang, Dominik Beck, Julie AI Thoms, Sofie Peirs, Kathy Knezevic, et al. 2016. “A Quantitative Proteomics Approach Identifies ETV6 and IKZF1 as New Regulators of an ERG-driven Transcriptional Network.” Nucleic Acids Research 44 (22): 10644–10661.
APA
Unnikrishnan, A., Guan, Y. F., Huang, Y., Beck, D., Thoms, J. A., Peirs, S., Knezevic, K., et al. (2016). A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network. NUCLEIC ACIDS RESEARCH, 44(22), 10644–10661.
Vancouver
1.
Unnikrishnan A, Guan YF, Huang Y, Beck D, Thoms JA, Peirs S, et al. A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network. NUCLEIC ACIDS RESEARCH. 2016;44(22):10644–61.
MLA
Unnikrishnan, Ashwin, Yi Fang Guan, Yizhou Huang, et al. “A Quantitative Proteomics Approach Identifies ETV6 and IKZF1 as New Regulators of an ERG-driven Transcriptional Network.” NUCLEIC ACIDS RESEARCH 44.22 (2016): 10644–10661. Print.
@article{8122205,
  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 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.},
  author       = {Unnikrishnan, Ashwin and Guan, Yi Fang and Huang, Yizhou and Beck, Dominik and Thoms, Julie AI and Peirs, Sofie and Knezevic, Kathy and Ma, Shiyong and Van de Walle, Inge 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 WH and Pimanda, John E},
  issn         = {0305-1048},
  journal      = {NUCLEIC ACIDS RESEARCH},
  keywords     = {ACUTE LYMPHOBLASTIC-LEUKEMIA,ACUTE MYELOID-LEUKEMIA,FACTOR-BINDING PROFILES,GENOME-WIDE ANALYSIS,STEM-CELL,DEFINITIVE HEMATOPOIESIS,HISTONE METHYLATION,MASS-SPECTROMETRY,HIGH EXPRESSION,GATA FACTORS},
  language     = {eng},
  number       = {22},
  pages        = {10644--10661},
  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},
  volume       = {44},
  year         = {2016},
}

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