MAPK/ERK2 phosphorylates ERG at serine 283 in leukemic cells and promotes stem cell signatures and cell proliferation

Huang, Y; Thoms, JAI; Tursky, ML; Knezevic, K; Beck, D; Chandrakanthan, V; Suryani, S; Olivier, J; Boulton, A; Glaros, EN; Thomas, SR; Lock, RB; MacKenzie, KL; Bushweller, JH; Wong, JWH; Pimanda, JE

MAPK/ERK2 phosphorylates ERG at serine 283 in leukemic cells and promotes stem cell signatures and cell proliferation

Thoms, JAI Tursky, ML Knezevic, K Beck, D Chandrakanthan, V Suryani, S Olivier, J Boulton, A Glaros, EN Thomas, SR Lock, RB MacKenzie, KL Bushweller, JH Wong, JWH Pimanda, JE

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Publication Type:: Journal Article
Citation:: Leukemia, 2016, 30 (7), pp. 1552 - 1561
Issue Date:: 2016-07-01

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Field	Value	Language
dc.contributor.author	Huang, Y https://orcid.org/0000-0002-7003-3110	en_US
dc.contributor.author	Thoms, JAI	en_US
dc.contributor.author	Tursky, ML	en_US
dc.contributor.author	Knezevic, K	en_US
dc.contributor.author	Beck, D	en_US
dc.contributor.author	Chandrakanthan, V	en_US
dc.contributor.author	Suryani, S	en_US
dc.contributor.author	Olivier, J	en_US
dc.contributor.author	Boulton, A	en_US
dc.contributor.author	Glaros, EN	en_US
dc.contributor.author	Thomas, SR	en_US
dc.contributor.author	Lock, RB	en_US
dc.contributor.author	MacKenzie, KL	en_US
dc.contributor.author	Bushweller, JH	en_US
dc.contributor.author	Wong, JWH	en_US
dc.contributor.author	Pimanda, JE	en_US
dc.date.available	2016-02-02	en_US
dc.date.issued	2016-07-01	en_US
dc.identifier.citation	Leukemia, 2016, 30 (7), pp. 1552 - 1561	en_US
dc.identifier.issn	0887-6924	en_US
dc.identifier.uri	http://hdl.handle.net/10453/98275
dc.description.abstract	© 2016 Macmillan Publishers Limited. Aberrant ERG (v-ets avian erythroblastosis virus E26 oncogene homolog) expression drives leukemic transformation in mice and high expression is associated with poor patient outcomes in acute myeloid leukemia (AML) and T-acute lymphoblastic leukemia (T-ALL). Protein phosphorylation regulates the activity of many ETS factors but little is known about ERG in leukemic cells. To characterize ERG phosphorylation in leukemic cells, we applied liquid chromatography coupled tandem mass spectrometry and identified five phosphorylated serines on endogenous ERG in T-ALL and AML cells. S283 was distinct as it was abundantly phosphorylated in leukemic cells but not in healthy hematopoietic stem and progenitor cells (HSPCs). Overexpression of a phosphoactive mutant (S283D) increased expansion and clonogenicity of primary HSPCs over and above wild-type ERG. Using a custom antibody, we screened a panel of primary leukemic xenografts and showed that ERG S283 phosphorylation was mediated by mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling and in turn regulated expression of components of this pathway. S283 phosphorylation facilitates ERG enrichment and transactivation at the ERG +85 HSPC enhancer that is active in AML and T-ALL with poor prognosis. Taken together, we have identified a specific post-translational modification in leukemic cells that promotes progenitor proliferation and is a potential target to modulate ERG-driven transcriptional programs in leukemia.	en_US
dc.relation.ispartof	Leukemia	en_US
dc.relation.isbasedon	10.1038/leu.2016.55	en_US
dc.subject.classification	Immunology	en_US
dc.subject.mesh	Hematopoietic Stem Cells	en_US
dc.subject.mesh	Cell Line, Tumor	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Leukemia	en_US
dc.subject.mesh	Serine	en_US
dc.subject.mesh	Cell Proliferation	en_US
dc.subject.mesh	MAP Kinase Signaling System	en_US
dc.subject.mesh	Protein Processing, Post-Translational	en_US
dc.subject.mesh	Binding Sites	en_US
dc.subject.mesh	Phosphorylation	en_US
dc.subject.mesh	Leukemia, Myeloid, Acute	en_US
dc.subject.mesh	Precursor T-Cell Lymphoblastic Leukemia-Lymphoma	en_US
dc.subject.mesh	Transcriptome	en_US
dc.subject.mesh	Transcriptional Regulator ERG	en_US
dc.title	MAPK/ERK2 phosphorylates ERG at serine 283 in leukemic cells and promotes stem cell signatures and cell proliferation	en_US
dc.type	Journal Article
utslib.citation.volume	7	en_US
utslib.citation.volume	30	en_US
utslib.for	1112 Oncology and Carcinogenesis	en_US
utslib.for	0903 Biomedical Engineering	en_US
utslib.for	1103 Clinical Sciences	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	7	en_US
pubs.publication-status	Published	en_US
pubs.volume	30	en_US

Abstract:

© 2016 Macmillan Publishers Limited. Aberrant ERG (v-ets avian erythroblastosis virus E26 oncogene homolog) expression drives leukemic transformation in mice and high expression is associated with poor patient outcomes in acute myeloid leukemia (AML) and T-acute lymphoblastic leukemia (T-ALL). Protein phosphorylation regulates the activity of many ETS factors but little is known about ERG in leukemic cells. To characterize ERG phosphorylation in leukemic cells, we applied liquid chromatography coupled tandem mass spectrometry and identified five phosphorylated serines on endogenous ERG in T-ALL and AML cells. S283 was distinct as it was abundantly phosphorylated in leukemic cells but not in healthy hematopoietic stem and progenitor cells (HSPCs). Overexpression of a phosphoactive mutant (S283D) increased expansion and clonogenicity of primary HSPCs over and above wild-type ERG. Using a custom antibody, we screened a panel of primary leukemic xenografts and showed that ERG S283 phosphorylation was mediated by mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling and in turn regulated expression of components of this pathway. S283 phosphorylation facilitates ERG enrichment and transactivation at the ERG +85 HSPC enhancer that is active in AML and T-ALL with poor prognosis. Taken together, we have identified a specific post-translational modification in leukemic cells that promotes progenitor proliferation and is a potential target to modulate ERG-driven transcriptional programs in leukemia.

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

http://hdl.handle.net/10453/98275