Overexpression of erg in cord blood progenitors promotes expansion and recapitulates molecular signatures of high erg leukemias

ABSTRACT High expression of the ETS family transcription factor ERG is associated with poor clinical outcome in acute myeloid leukemia (AML) and acute T-cell lymphoblastic leukemia (T-ALL).

In murine models, high ERG expression induces both T-ALL and AML. However, no study to date has defined the effect of high ERG expression on primary human hematopoietic cells. In the present

study, human CD34+ cells were transduced with retroviral vectors to elevate ERG gene expression to levels detected in high ERG AML. RNA sequencing was performed on purified populations of

transduced cells to define the effects of high ERG on gene expression in human CD34+ cells. Integration of the genome-wide expression data with other data sets revealed that high ERG drives

an expression signature that shares features of normal hematopoietic stem cells, high ERG AMLs, early T-cell precursor-ALLs and leukemic stem cell signatures associated with poor clinical

outcome. Functional assays linked this gene expression profile to enhanced progenitor cell expansion. These results support a model whereby a stem cell gene expression network driven by high

ERG in human cells enhances the expansion of the progenitor pool, providing opportunity for the acquisition and propagation of mutations and the development of leukemia. Access through your

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cytospins, donors and staff of the CB banks at the Prince of Wales and Royal North Shore Hospitals for CBs, Simon Downes, Soo Min Heng and Joel Poder from Medical Physics, Department of

Radiation Oncology, Prince of Wales Hospital for calibration of the bio-irradiator. This work was funded by the National Health and Medical Research Council (Australia), Leukaemia Foundation

(Australia) and the Cancer Institute of NSW. MLT received scholarships from the Prince of Wales Clinical School and the Children’s Cancer Institute, Australia. Children’s Cancer Institute

is affiliated with University of New South Wales and Sydney Children’s Hospital Network. The authors also thank the Australian Research Council (JWHW), Children with Cancer (UK), Israel

Science Foundation and Waxman Cancer Research Foundation (to SI). This work was funded by the National Health and Medical Research Council (Australia) and Leukaemia Foundation (Australia).

AUTHOR CONTRIBUTIONS MLT, DB, JAIT, YH, AK, AU, KK, KE, LAR, EL and LG performed experiments and analyzed data. JO, KLM, JEP and JWHW analyzed data, JM and RBL provided essential reagents,

MLT, DB, JAIT, SI, KLM and JEP wrote the paper. AUTHOR INFORMATION Author notes * M L Tursky, D Beck, J A I Thoms, K L MacKenzie and J E Pimanda: These authors contributed equally as first

authors. * These authors contributed equally as senior authors. AUTHORS AND AFFILIATIONS * Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW, Sydney,

Australia M L Tursky, D Beck, J A I Thoms, Y Huang, A Unnikrishnan, K Knezevic, J W H Wong & J E Pimanda * Children’s Cancer Institute Australia, Lowy Cancer Research Centre, UNSW,

Sydney, Australia M L Tursky, A Kumari, K Evans, L A Richards, E Lee, R B Lock & K L MacKenzie * Department of Obstetrics and Gynaecology, Royal North Shore Hospital, University of

Sydney, Sydney, Australia J Morris * Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel L Goldberg & S Izraeli * Department of Human Molecular Genetics and

Biochemistry, Tel Aviv University, Tel Aviv, Israel L Goldberg & S Izraeli * School of Mathematics and Statistics, UNSW, Sydney, Australia J Olivier * Department of Haematology, Prince

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DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies this paper on the Leukemia website SUPPLEMENTARY

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Thoms, J. _et al._ Overexpression of ERG in cord blood progenitors promotes expansion and recapitulates molecular signatures of high ERG leukemias. _Leukemia_ 29, 819–827 (2015).

https://doi.org/10.1038/leu.2014.299 Download citation * Received: 21 May 2014 * Revised: 04 September 2014 * Accepted: 03 October 2014 * Published: 13 October 2014 * Issue Date: April 2015

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