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Oncogenes, Fusion Genes and Tumor Suppressor Genes

The E2A-HLF oncogenic fusion protein acts through Lmo2 and Bcl-2 to immortalize hematopoietic progenitors

Abstract

The oncogenic fusion protein E2A–HLF is a chimeric transcription factor that arises from the t(17;19) translocation in childhood B-cell acute lymphoblastic leukemias (B-precursor ALL) and is associated with very poor outcome. We show that retroviral-mediated expression of E2A–HLF alone is sufficient to immortalize primary lymphoid progenitors. We identify Lmo2 and Bcl-2 as direct target genes downstream of E2A–HLF. We use real-time PCR analysis to show that LMO2 and BCL-2 expression is preferentially upregulated both in biopsy material from t(17;19) B-precursor ALL patients and lymphoid cell lines derived from t(17;19) leukemias. Co-expression of Lmo2 and Bcl-2 was sufficient to immortalize lymphoid progenitor cells resulting in a similar phenotype to that induced by E2A–HLF alone. Both shRNA-mediated knockdown of Lmo2 expression and pharmacological inhibition of BCL-2 function in E2A–HLF immortalized cells severely compromised their viability. These data suggest that both Lmo2 and Bcl-2 are required for the action of E2A–HLF in leukemogenesis.

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Acknowledgements

We thank Professor Jean-Pierre Bourquin, Zurich, Switzerland, Professor Andy Hall, Newcastle, UK and Professor Martin Stanulla, Kiel, Germany for permission to use t(17;19) patient material. We are grateful to the staff of the ICH Gene Microarray Centre, Animal Facility and Flow Cytometry. We thank Dr J Ham for helpful comments and evaluation of the manuscript. We thank Abbott Laboratories for the gift of ABT-737. This work was funded by the Audrey Callaghan Fellowship, the Leukaemia Research Fund and Children with Leukaemia.

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Correspondence to H J M Brady.

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de Boer, J., Yeung, J., Ellu, J. et al. The E2A-HLF oncogenic fusion protein acts through Lmo2 and Bcl-2 to immortalize hematopoietic progenitors. Leukemia 25, 321–330 (2011). https://doi.org/10.1038/leu.2010.253

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