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Acute Leukemias

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.

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Acknowledgements

We thank Gillian Rozenberg for the photographs of the 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.

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Correspondence to K L MacKenzie or J E Pimanda.

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Tursky, M., Beck, D., 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

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